Months Of Insulin Treatment Research Articles

A mathematical model for ketosis-prone diabetes suggests the existence of multiple pancreatic β-cell inactivation mechanisms.

Ketosis-prone diabetes mellitus (KPD) is a subtype of type 2 diabetes, which presents much like type 1 diabetes, with dramatic hyperglycemia and ketoacidosis. Although KPD patients are initially insulin-dependent, after a few months of insulin treatment, ~ 70% undergo near-normoglycemia remission and can maintain blood glucose without insulin, as in early type 2 diabetes or prediabetes. Here, we propose that these phenomena can be explained by the existence of a fast, reversible glucotoxicity process, which may exist in all people but be more pronounced in those susceptible to KPD. We develop a simple mathematical model of the pathogenesis of KPD, which incorporates this assumption, and show that it reproduces the phenomenology of KPD, including variations in the ability for patients to achieve and sustain remission. These results suggest that a variation of our model may be able to quantitatively describe variations in the course of remission among individuals with KPD.

Efficacy of combination therapy with GABA, a DPP-4i and a PPI as an adjunct to insulin therapy in patients with type 1 diabetes.

The purpose of this retrospective clinic chart review study was to determine the potential of a combination therapy (CT) consisting of γ-aminobutyric acid (GABA), a dipeptidyl peptidase-4 inhibitor (DPP-4i), and a proton pump inhibitor (PPI) to improve glycemic control as an adjunct to insulin therapy in patients with type 1 diabetes (T1D). Nineteen patients with T1D on insulin therapy were treated with additional CT in oral form. Fasting blood glucose (FBG), HbA1c, insulin dose-adjusted HbA1c (IDA-A1c), daily insulin dose, insulin/weight ratio (IWR), and fasting plasma C-peptide were measured after 26-42 weeks of treatments. FBG, HbA1c, IDA-A1c, insulin dose and IWR were all significantly decreased while plasma C-peptide was significantly increased by the CT. Treatment outcomes were further analyzed by separation of the 19 patients into two groups. One group started on the CT within 12 months of insulin treatment (early therapy, 10 patients) and another group started on this therapy only after 12 months of insulin treatment (late therapy, 9 patients). FBG, IDA-A1c, insulin dose, and IWR decreased significantly in both the early and late CT groups, however to a better extent in the early therapy group. Moreover, plasma C-peptide increased significantly only in the early therapy group, and 7 of the 10 patients in this group were able to discontinue insulin treatment while maintaining good glycemic control to study end compared with none of the 9 patients in the late therapy group. These results support the concept that the combination of GABA, a DPP-4i and a PPI as an adjunct to insulin therapy improves glycemic control in patients with T1D, and that the insulin dose required for glycemic control can be reduced or even eliminated in some patients receiving this novel therapy.

Alpha and Beta Cell Dysfunction Improves With Effective Insulin Therapy in Treatment Naive Type 2 Diabetes - a Prospective Observational Study

: Type 2 diabetes mellitus is characterized by insulin resistance and progressive beta cell decline. Elevated glucagon levels and impaired incretin axis also contribute to the poor glycemic status. Early intensive glycemic control, reduces long-term vascular complications and may preserve β-cell function. Clinical studies of effect of early insulin therapy on combined alpha and beta cell function are lacking. Objective: To determine the effect of early insulin therapy on combined alpha and beta cell dysfunction (islet cell dysfunction) in newly diagnosed type 2 diabetes. Methods: 56 newly diagnosed type 2 diabetes patients, attending the endocrinology OPD at a tertiary teaching hospital were enrolled in this treatment related follow up study after institutional ethical committee clearance, conducted between May 2017 to December 2018. Patients with HbA1C > 8.5% to <12.5% (n=56) were included in the study. Metabolic (FPG, PPG, HbA1c), and Hormonal parameters (plasma glucagon levels,fasting and 2 hour mixed meal stimulated C peptide and levels) were assessed both at baseline and after 6 months of insulin treatment. Initiating dose of insulin was 0.5 U/kg/day and the dose was titrated according to FPG and 2 hr PPG in order to maintain glycemic goals as per ADA standards. Results: The study included 56 subjects with mean age of 41.24 ± 5.64 years and a mean BMI of 25.5 kg/m2. At the end of 6 months of the study, a significant reduction in the mean FPG, PPG, HbA1C were observed,[FPG (139±14.47 mg/dl), PPG (179.89 ± 19.42mg/dl),HbA1c (7.54± 0.63%)] as compared to baseline mean FPG, (216.30 ± 42.35 mg/dl),2 hour PPG (338.44 ±62.89 mg/dl), HbA1C (10.39 ± 1.56 %) (p <0.001). Baseline glucagon levels were high (197.68± 49.09 pg/ml), and were significantly reduced at 6 months of insulin therapy (107.06±49.09 pg/ml).(p <0.001). In comparison to the baseline a significant increase in both fasting (0.73±0.27 ng/ml) and stimulated c-peptide (1.54±1.02 ng/ml) (p<0.001) levels was observed at end of the study. Conclusion: Combined alpha and beta cell (Islet) dysfunction prevails in newly diagnosed T2DM. And early insulin therapy significantly improves both these defects. The documentation of this novel beneficial effect on islet cell dysfunction in our study strengthens the concept of early insulin therapy in newly diagnosed Type 2 diabetes patients.

Study of the Effect of Early Insulin Therapy on Inflammation and Its Correlation With Glucotoxicity in Newly Diagnosed T2DM

Abstract Diabetes is a chronic metabolic and inflammatory disorder resulting in long term vascular complications. Glucotoxicity has been proposed to aggravate inflammatory stress. In this background,effect of early insulin therapy on inflammatory markers in relation to the glycemic status could be relevant in the newly diagnosed Type 2DM patients. Clinical studies highlighting this pathophysiologic aspect are sparse. Objective: To determine the effect of early insulin therapy in newly diagnosed patients with type 2 diabetes mellitus on inflammatory markers and glucotoxicity. Methods: 40 newly diagnosed type 2 diabetes patients, attending the endocrinology OPD at a tertiary teaching hospital were enrolled in this treatment related follow up study after institutional ethical committee clearance, conducted between May 2019 to February 2020. Patients with HbA1C &amp;gt; 8.5% to &amp;lt;12.5% were included in the study. Metabolic (FPG, PPG, HbA1c), and inflammatory parameters (Serum IL-6, Serum TNF alpha levels) were assessed both at baseline and after 9 months of insulin treatment. A simple,conventional twice daily premixed insulin was initiated at a starting dose of insulin at 0.5 U/kg/day and the dose was titrated according to FPG and 2 hr PPG in order to maintain glycemic goals as per ADA standards. Results: The study included 40 subjects with a mean age of 43.9 years and a mean BMI of 26.46 kg/m2. At the end of 9 months of the study, mean FPG, PPG, HbA1C were significantly reduced [FPG (118.45± 24.74mg/dl), PPG (152± 25 mg/dl), HbA1c (6.67± 0.42%)] as compared to baseline [FPG, (218.4± 37.84mg/dl), PPG (307±62mg/dl), HbA1C (9.95± 1.39%) (p &amp;lt;0.001). A statistically significant decrease in inflammatory markers like IL6, TNF alpha, from baseline to 9 months [.IL6 5.365±1.465 to 2.819±0.697 pg/ml, S.TNF alpha 36.476±16.902 to 11.274±3.712 pg/ml.] (p &amp;lt;0.001) was observed. Correlation studies revealed at 9 months, a highly significant positive correlation between FPG, PPG and IL6 and TNF alpha levels (p&amp;lt;0 .001), in comparison with baseline (p&amp;lt; 0.05). However IL6 levels significantly correlated with HBA1c both at baseline and at 9 months (p&amp;lt;0.05), whereas only a non significant positive correlation with TNF alpha was observed. Conclusion: Early Insulin treatment has beneficial effect on both Inflammation and glucotoxicity in newly diagnosed Type2 DM. Effective, simple and early insulin regimen offers a pathophysiologic based therapeutic perspective aiming at improving the natural course of diabetes.

PDB122 REAL-WORLD INSULIN THERAPY IN GERMAN TYPE 2 DIABETES MELLITUS PATIENTS: PATIENT CHARACTERISTICS, TREATMENT PATTERNS AND INSULIN DOSAGE

A substantial share of type 2 diabetes mellitus (T2DM) patients receives insulin. However, little is known about the real-world treatment patterns around insulin initiation. This was a retrospective claims data analysis. T2DM patients who initiated an insulin therapy between 01/01/2013 and 31/12/2015 were identified in the German AOK PLUS dataset. For validation of results, additional data on a similar T2DM patient population were collected in a Germany-wide medical chart review. 284,878 T2DM patients were identified. 27,340 (9.6%) of these initiated an insulin treatment during the inclusion period (mean age: 72.2 years; 51.4% female). Mean/median weight | BMI of patients with available clinical data was 85.8/84.0 kg (SD:18.9) | 30.6/29.8 kg/m2 (SD:6.1) at baseline. Mean/median HbA1c-value at baseline was 8.4/8.0% (SD: 1.8). Most commonly prescribed antidiabetic drugs (AD) within 6 months before insulin initiation were metformin (MET; 54.0%), DPP-4 inhibitors (DPP-4i; 37.6%) and sulfonylureas (SU; 29.5%). 23.2% of patients did not receive any AD prescription within 6 months before insulin initiation. 10,953 of above 27,340 insulin starters (40.1%) initiated their insulin therapy without concomitant ADs (insulin monotherapy); 43% of these patients did not receive any AD before insulin initiation. Of the remaining 16,387 patients (59.9%), 4,070 patients (14.9%) received MET only as concomitant AD, 6,385 (23.4%) received MET plus at least one further AD, and 5,932 (21.7%) received at least one further AD excluding MET. Throughout the first year of treatment, prescribed insulin dosage increased over time, resulting in approximately 43.3-77.9 IUs per observed patient day after 12 months of insulin treatment. Characteristics of German T2DM patients initiating insulin deviate substantially from the average German population, especially in terms of weight. We identified an unexpectedly high number of patients without previous AD therapy receiving insulin monotherapy, which is not in line with the clinical guidelines.

Weight gain in insulin-treated patients by body mass index category at treatment initiation: new evidence from real-world data in patients with type 2 diabetes.

To evaluate, in patients with type 2 diabetes (T2DM) treated with insulin, the extent of weight gain over 2 years of insulin treatment, and the dynamics of weight gain in relation to glycaemic achievements over time according to adiposity levels at insulin initiation. Patients with T2DM (n = 155 917), who commenced insulin therapy and continued it for at least 6 months, were selected from a large database of electronic medical records in the USA. Longitudinal changes in body weight and glycated haemoglobin (HbA1c) according to body mass index (BMI) category were estimated. Patients had a mean age of 59 years, a mean HbA1c level of 9.5%, and a mean BMI of 35 kg/m2 at insulin initiation. The HbA1c levels at insulin initiation were significantly lower (9.2-9.4%) in the obese patients than in patients with normal body weight (10.0%); however, the proportions of patients with HbA1c >7.5% or >8.0% were similar across the BMI categories. The adjusted weight gain fell progressively with increasing baseline BMI category over 6, 12 and 24 months (p < .01). The adjusted changes in HbA1c were similar across BMI categories. A 1% decrease in HbA1c was associated with progressively less weight gain as pretreatment BMI rose, ranging from a 1.24 kg gain in those with a BMI <25 kg/m2 to a 0.32 kg loss in those with a BMI > 40 kg/m2 . During 24 months of insulin treatment, obese patients gained significantly less body weight than normal-weight and overweight patients, while achieving clinically similar glycaemic benefits. These data provide reassurance with regard to the use of insulin in obese patients.

Clinical outcomes and resource use after 24months of insulin therapy in Turkish patients with type 2 diabetes: subgroup analysis of the TREAT study.

This study evaluated levels of metabolic control, resource use and quality of life in Turkish patients with type 2 diabetes initiated on insulin in routine care. The prospective, observational TREAT study evaluated patients from five different countries who were initiated on insulin and followed for 24 months. In this paper, we present the results of a cohort analysis specific to Turkish patients from the study. A total of 211 patients in the Turkish multicenter cohort [male patients 50.2%, age 56.5 year±8.9 SD, body mass index (BMI) 30.6 kg/m2±5.4 SD, diabetes duration 9.7 year±5.9 SD] initiated insulin at baseline. Oral antidiabetic drugs had been used by 93.4% of patients prior to insulin initiation, and 65.9% had used more than one regimen. Pre-existing metformin therapy was continued by 68.7% of patients after insulin initiation. In the three most common insulin regimens, glycosylated haemoglobin (HbA1C) declined over 24 months from 10.27% to 7.82% (long/intermediate acting), from 10.82% to 7.52% (premixed) and from 10.42% to 7.67% (basal-bolus). Less than 25% achieved a glycaemic goal of HbA1C≤7.0% and changes in insulin dose or regimen rarely occurred. Premixed insulin regimens were associated with greatest weight gain. Hypoglycaemic episodes were reported by more patients at 3, 6 and 12 months than at baseline or at 18 or 24 months. Healthcare use increased over baseline levels in the first 6 months, but was closer to baseline levels at subsequent assessments. Patient recorded health profiles improved after initiating insulin, particularly quality of life scores related to psychological distress and pain/discomfort. Morisky scores predictive of medication adherence and treatment persistence also improved. In Turkish patients with type 2 diabetes, metabolic control remained suboptimal after initiating insulin as part of routine care even after 24 months of insulin treatment. Apparent shortcomings in routine care in most patients included a high baseline HbA1C because of delayed insulin initiation and an unwillingness to individualise insulin regimens.

Evaluation of insulin initiation on resource utilization and direct costs of treatment over 12 months in patients with type 2 diabetes in Europe: results from INSTIGATE and TREAT observational studies

Objectives:To describe the changes in resource utilization in seven European countries (Germany, Greece, Portugal, Romania, Sweden, Spain, and Turkey) and direct costs in four European countries (Germany, Spain, Sweden, and Greece) over the first 12 months of insulin treatment in patients with type 2 diabetes mellitus (T2DM).Methods:INSTIGATE and TREAT (2005–2010) were non-interventional, prospective, observational studies in patients with T2DM and initiating insulin for the first time. A 6-month retrospective data capture was conducted at baseline (insulin initiation) followed by prospective data collections at ∼3, 6, and 12 months. Statistical analyses were descriptive; estimated costs are presented as nominal values.Results:This study presents data for 1450 patients. Overall, in the first 6 months after insulin initiation, the use and cost of blood glucose monitoring and insulin increased, while the cost of oral diabetic medication decreased. Contributors to total direct costs differed between countries. Ranges of total mean direct costs over the 6-month period before insulin initiation were €489.10–€658.50 (Greece–Spain); 0–6 months after insulin initiation, €573.40–€1084.70 (Greece–Spain); and 6–12 months after insulin initiation, €495.80–€859.30 (Greece–Germany). Thus, the mean cost of treatment increased in all countries in the first 6 months after insulin initiation and then returned to baseline except in Germany.Limitations:Overall, 15% of patients were lost to follow-up over 12 months. Costs were not pro-rated to account for variation of visits. Participating centres may not have been fully representative of all levels of care.Conclusions:Contributors to total cost differed between countries, potentially reflecting local clinical practice patterns and insulin regimens. In each country, mean direct total costs of T2DM care increased during the first 6 months after insulin initiation and decreased thereafter.

Direct healthcare costs and clinical outcomes after insulin initiation in patients with type 2 diabetes mellitus in Spain: 24-month follow-up data from the INSTIGATE study

Abstract Background and objective The INSTIGATE study assessed healthcare costs and clinical outcomes in patients with type 2 diabetes mellitus starting insulin therapy in Spain over a 24-month follow up period. Material and methods This was an observational, non-interventional, prospective, multicenter study. Costs incurred in the previous 6 months were assessed at each visit. Results A total of 172 patients with a mean body mass index of 29.6 kg/m 2 , a mean [standard deviation] duration of diabetes of 10.9 [7.0] years and a hemoglobin A 1c value of 9.2% [1.5%] were followed up for at least 12 and up to 24 months. Direct costs were assessed from the perspective of the Spanish healthcare system. Long/intermediate-acting insulin alone was started in 116 patients (67.4%). After 6, 12, and 24 months of insulin treatment, mean [SD] intraindividual changes from baseline in hemoglobin A 1c were −1.9% [1.65%], −1.6 [1.73%], and −1.5% [1.76%] respectively. Mean (median) total diabetes-related healthcare costs per patient increased from €659 (€527) to €1.085 (€694) 6 months after insulin initiation, decreased to €646 (€531) after 12 months, and increased again after 24 months to €667 (€539). Insulin/oral antidiabetics, primary/specialized care, and blood glucose monitoring accounted for 41%, 26%, and 19% of total cost at 24 months respectively. Conclusions Clinical parameters of these patients with type 2 diabetes mellitus improved following insulin initiation. After a temporary increase, direct healthcare costs of diabetes care returned to baseline values at the end of the follow-up period.

Costes directos sanitarios y resultados clínicos tras el inicio del tratamiento con insulina en pacientes con diabetes mellitus tipo 2 en España: datos de 24 meses de seguimiento del estudio INSTIGATE

Background and objectiveThe INSTIGATE study assessed healthcare costs and clinical outcomes in patients with type 2 diabetes mellitus starting insulin therapy in Spain over a 24-month follow up period. Material and methodsThis was an observational, non-interventional, prospective, multicenter study. Costs incurred in the previous 6 months were assessed at each visit. ResultsA total of 172 patients with a mean body mass index of 29.6kg/m2, a mean [standard deviation] duration of diabetes of 10.9 [7.0] years and a hemoglobin A1c value of 9.2% [1.5%] were followed up for at least 12 and up to 24 months. Direct costs were assessed from the perspective of the Spanish healthcare system. Long/intermediate-acting insulin alone was started in 116 patients (67.4%). After 6, 12, and 24 months of insulin treatment, mean [SD] intraindividual changes from baseline in hemoglobin A1c were -1.9% [1.65%], -1.6 [1.73%], and -1.5% [1.76%] respectively. Mean (median) total diabetes-related healthcare costs per patient increased from €659 (€527) to €1.085 (€694) 6 months after insulin initiation, decreased to €646 (€531) after 12 months, and increased again after 24 months to €667(€539). Insulin/oral antidiabetics, primary/specialized care, and blood glucose monitoring accounted for 41%, 26%, and 19% of total cost at 24 months respectively. ConclusionsClinical parameters of these patients with type 2 diabetes mellitus improved following insulin initiation. After a temporary increase, direct healthcare costs of diabetes care returned to baseline values at the end of the follow-up period.

Contribution of change in glycosylated haemoglobin to insulin-associated weight gain: results of a longitudinal study in type 2 diabetic patients

To investigate the contribution of glycosylated haemoglobin change (HbA1c) on body weight in patients with type 2 diabetes after start of insulin therapy. We analysed 122 individual weight-profiles in relation to the change in HbA1c per se in these patients up to 36months after the start of insulin therapy. Data were analysed separately for the first 9months after commencement of insulin therapy and for the period thereafter. Within the first 9months of insulin therapy mean body weight increased by 0.52kg per month. HbA1c decreased from 9.9±1.8 to 7.9±1.3%. Only 12% of the initial weight gain could be attributed to the change in HbA1c. Furthermore, the mean monthly increase in body weight gain was reduced by 0.006kg for every 1kg higher body weight at baseline. From 9 to 36months after start of insulin therapy, body weight increased by 0.1kg/month, which was independent of change in HbA1c. Improvement of glycaemic control per se contributes little to initial weight gain after start of insulin therapy in patients with T2DM. After 9months of insulin treatment, weight gain is unrelated to change in glycosylated haemoglobin. Other factors have to be responsible for weight gain after start of insulin therapy.

Longitudinal epitope analysis of insulin-binding antibodies in type 1 diabetes

Autoantibodies to insulin (IAA) are one of the first markers of the autoimmune process leading to type 1 diabetes (T1D). While other autoantibodies in T1D have been studied extensively, relatively little is known about IAA and their binding specificities, especially after insulin treatment is initiated. We hypothesize that insulin antibodies (IA) that develop upon initiation of insulin treatment differ in their epitope specificities from IAA. We analysed insulin antibody binding specificities in longitudinal samples of T1D patients (n = 49). Samples were taken at clinical diagnosis of disease and after insulin treatment was initiated. The epitope specificities were analysed using recombinant Fab (rFab) derived from insulin-specific monoclonal antibodies AE9D6 and CG7C7. Binding of radiolabelled insulin by samples taken at onset of the disease was significantly reduced in the presence of rFab CG7C7 and AE9D6. rFab AE9D6 competed sera binding to insulin significantly better than rFab CG7C7 (P = 0.02). Binding to the AE9D6-defined epitope in the initial sample was correlated inversely with age at onset (P = 0.005). The binding to the AE9D6-defined epitope increased significantly (P < 0.0001) after 3 months of insulin treatment. Binding to the CG7C7-defined epitope did not change during the analysed period of 12 months. We conclude that epitopes recognized by insulin binding antibodies can be identified using monoclonal insulin-specific rFab as competitors. Using this approach we observed that insulin treatment is accompanied by a change in epitope specificities in the emerging IA.

Treatment satisfaction after commencement of insulin in Type 2 diabetes

Fifty patients with Type 2 diabetes were recruited for a study assessing treatment satisfaction and well-being, following commencement on insulin during routine clinical care. A month after starting insulin, participants completed a Diabetes Treatment Satisfaction Questionnaire (DTSQ) and a Well-being Questionnaire. At seven months, the same questionnaires and clinical measurements were repeated and, in addition, patients completed a Diabetes Treatment Satisfaction Questionnaire (change) (DTSQc). Mean HbA 1c decreased from 9.69 to 8.26% ( P < 0.001), and the lipid profile showed a corresponding improvement. BMI increased from 30.9 to 32.0 kg m −2 ( P < 0.001). Perceived frequency of hyperglycaemia decreased ( P = 0.021), correlating with the change in HbA 1c ( r = 0.399, P = 0.006). The DTSQc showed improvements at seven months in scores for treatment satisfaction, convenience, flexibility, understanding of diabetes, willingness to recommend the treatment to others, and satisfaction to continue current treatment (all P < 0.001). There was no relationship between weight gain, HbA1c and total or subscale scores. In summary, after seven months of insulin treatment, patients reported positive changes in their perception of treatment satisfaction. These findings, in conjunction with the known health benefits of improved glycaemic control, should encourage practitioners to consider insulin early in the management of Type 2 diabetes.

Calcium dobesilate attenuates vascular injury and the progression of diabetic retinopathy in streptozotocin-induced diabetic rats.

Diabetic retinopathy (DR) is a highly specific vascular complication of type 1 and type 2 diabetes mellitus. Calcium dobesilate (DOBE) has been tested in the treatment of diabetic retinopathy showing a slowdown of the progression of the disease after long-term oral treatment. The aim of this study was to determine the effects of DOBE on vascular and diabetic retinopathy in streptozotocin (STZ) diabetic rats. Diabetes was induced in wistar rats by the administration of STZ (60 mg/kg, i.p.). Rats were divided into three groups (n = 30). Group 0 (GO): nondiabetic rats. Group 1 (G1): 14 months of insulin treatment after diabetes development. Group 2 (G2): 14 months of insulin treatment after diabetes development plus DOBE (500 mg/kg/day). At the end of the treatment, vascular reactivity was tested. The study of the vascularization of the retina was performed on wholemounts of trypsin retinal digest preparations and retinal sections. Relaxation induced by acetylcholine decreased in the aorta arteries from diabetic rats but it was restored to control values in the DOBE-treated group (71.8 +/- 4.5%, 53.3 +/- 0.5%, 67.4 +/- 4.6% in group 0, 1 and 2 respectively). DOBE treatment also restored noradrenaline (1.08 +/- 0.05 g, 1.70 +/- 0.08 g, 1.13 +/- 0.05 g in group 0, 1 and 2 respectively) and caffeine-induced contractions. Diabetic state did not cause any alteration in mesenteric arteries. The analysis of the retinal digests showed vascular tortuosity, acellular capillaries, focal accumulations of capillaries and reduction of the number of pericytes in G1. The vascular changes observed in G2 seem to be intermediate between the control and the diabetic rats. We showed that long-term treatment with DOBE attenuated the progression of diabetic retinopathy and the alterations in vascular reactivity in streptozotocin-induced diabetic rats.

Immune responses to glutamic acid decarboxylase and insulin in patients with gestational diabetes.

Pregnancy is a natural state of immunoprotection and tolerance. We studied subjects with gestational diabetes (GDM) to evaluate the influence of pregnancy on the humoral immune response to the autoantigen GAD and to injected insulin. Antibodies against glutamic acid decarboxylase (GADA) subclasses and epitope reactivity were determined in 34 GADA-positive pregnant patients with GDM, in 20 GADA-positive relatives of people with TID and in 25 GADA-positive patients with newly diagnosed TID. Partum levels of insulin antibodies (IA), IgG1- and IgG4-IA were measured in 131 women with GDM treated with human insulin from the time of diabetes diagnosis (including 22 with GADA) and were compared to 19 patients with TID after 3 months of insulin treatment. GADA titre and subclasses were similar among all groups. GADA in GDM patients bound fewer epitopes than GADA in relatives of patients with TID (all epitopes being present in 23%versus 65%, P < 0.01). In particular, antibodies to the minor GADA epitopes GAD6596-249, GAD651-100 and GAD67 were less frequent in patients with GDM compared to relatives (P < 0.01). Antibodies to insulin (IA) were found in 17% of patients with GDM. They were more frequent in GDM patients with GADA compared to GADA-negative patients (41%versus 12%, P < 0.005). IgG1 was the dominant insulin antibody subclass response in both patients with GDM and TID but levels of IgG1-IA and IgG4-IA were significantly lower in patients with GDM compared to patients with TID (P < 0.004). Antibody responses in women with gestational diabetes appear to be dampened and restricted, but without change in subclass usage.

Reduced number of circulating monocytes after institution of insulin therapy--relevance for development of atherosclerosis in diabetics?

Twelve patients with Type II diabetes mellitus, insufficiently controlled with oral hypoglycemic agents, were studied before, after 2 months, and after 4 months on insulin therapy. For comparison the same variables were also studied in 10 healthy subjects. From the start, in the diabetic group, the authors found alterations in the hemorheologic parameters indicated by increased values for whole blood viscosity, plasma viscosity, red cell transit time (RCTT), and decreased values for white cell initial relative filtration rate (IrFR). In hematologic parameters they found increased values for mean corpuscular volume (MCV), leukocyte count, counts of neutrophils and monocytes, and a decreased count of lymphocytes. They also found increased values in the lipid parameters P-triglycerides and Apo B/Apo A-I ratio, risk factors of coronary atherosclerosis. After 4 months of insulin treatment whole blood and plasma viscosity were still increased, but there was a partial improvement of lipoprotein abnormalities. Red and white cell filterability, however, tended to normalize. These results indicate that changes in blood cell filterability do not necessarily influence in vitro measurements of blood viscosity. The change in RCTT during the insulin treatment was associated with a decreased MCV and the change in white cell IrFR with a decrease in the number of monocytes. This change of white cell filterability during insulin therapy, probably due to a reduced number of monocytes, may be of interest in the study of atherosclerosis and circulatory disease in diabetics.

Different faces of non‐autoimmune diabetes of infancy

The aim of this report is to describe four cases of non‐autoimmune diabetes that presented in infancy. Three had transient neonatal diabetes mellitus (TNDM) with diabetic ketoacidosis at onset, followed by complete remission after several months of insulin treatment. While the fourth case was initially diagnosed as TNDM, she had renal, hepatic and pancreatic dysplasia. These cases illustrate that diabetes in infants can be difficult to diagnose and that patients with TNDM can have a recurrence of diabetes several years later.

Insulin versus glipizide treatment in patients with non-insulin-dependent diabetes mellitus: Effects on blood pressure and glucose tolerance

Insulin resistance that exists in patients with essential hypertension and in those with non-insulin-dependent diabetes mellitus (NIDDM) may be the common denominator for the impaired glucose homeostasis and elevated blood pressure (BP) levels in patients with NIDDM. Therefore, treatment that improves insulin action may also improve BP levels. Consequently, a four-phase (glipizide v insulin) cross-over design study was conducted to determine a better effect of glipizide treatment on insulin sensitivity and the effect this has on BP in 19 NIDDM patients. Patients were subjected to 1 month of diet only (phase I) followed by 3 months of glipizide treatment (phase II), then an additional 1 month of diet only (phase III), and finally 3 months of insulin treatment (phase IV). At the end of phases I, II, and IV oral glucose tolerance tests (OGTT) were performed and plasma glucose, insulin, and C-peptide levels were analyzed. Fasting plasma glucose, insulin, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides, glycated hemoglobin, fructosamine, and 2-h postprandial plasma glucose were also analyzed at each phase. Supine and sitting BP levels and body weights were determined biweekly during the study. With the exception of higher plasma insulin and C-peptide levels during the OGTT (area under the curve) in phase IV (insulin) v phase II (glipizide) (both P < .05), and higher fasting plasma insulin levels (P < .06), there were no consistently significant metabolic differences between phases IV and II.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoantibodies to insulin and to proinsulin in type 1 diabetic patients and in at-risk probands differentiate only little between both antigens.

To answer the question whether insulin or proinsulin would be the true antigen for both insulin and proinsulin autoantibodies, displacement experiments of 125I-insulin and -proinsulin binding with both unlabeled antigens were performed in sera of four groups of antibody-positive probands: first-degree relatives of Type 1 diabetic patients, pre-Type 1 diabetic persons, recent-onset Type 1 diabetic patients, insulin-treated Type 1 diabetic patients. In subjects who were primarily screened to constitute these groups, prevalences of insulin and proinsulin autoantibodies were nearly identical. In antibody-positive sera, 125I-insulin and -proinsulin binding values in general were closely correlated to each other with regression coefficients near 1.0. In all groups of probands, mean values of 125I-insulin and -proinsulin binding did not significantly differ. With the exception of a few sera, insulin and proinsulin antibodies differentiated only little between both antigens. Epitopes of the insulin molecule are therefore preferred. Nevertheless, insulin and proinsulin autoantibodies are not completely identical nor are insulin autoantibodies merely a subgroup of proinsulin autoantibodies: In each group, in the mean, insulin antibodies as well as proinsulin antibodies reacted somewhat (but significantly) stronger with their respective antigen. In some cases a distinct (relative) specificity for either antigen of insulin and proinsulin autoantibodies were observed, the latter being still present after some months of insulin treatment. In conclusion, despite detectable differences in antigen specificity, insulin and proinsulin autoantibodies seem to be equally potent markers of Type 1 diabetes mellitus.

Haemostatic Abnormalities Persist Despite Glycaemic Improvement by Insulin Therapy in Lean Type 2 Diabetic Patients

Diabetes mellitus is associated with disturbances of the hemostatic system, which might contribute to the development of diabetic vascular disease. We investigated the effect of metabolic improvement by insulin therapy on the haemostatic system in 61 patients with type 2 diabetes mellitus and secondary sulfonylurea failure compared with 45 healthy control subjects matched for age, sex and BMI. Median age was 65, median diabetes duration 10 years. Median HbA1c (10%) and fructosamine (4.0 mM) levels were elevated before induction of therapy and decreased significantly within 6 months of insulin treatment to 7.5% and 3.0 mM, respectively (p < 0.0001). Compared with control subjects, median plasma levels of fibrinogen (317 vs 286 mg/dl), coagulation factor VII activity (1.1 vs 0.89 U/l), von Willebrand factor (1.6 vs 1.3 U/l), D-dimer (105 vs 86 micrograms/l), protein C:Ag (1.24 vs 0.95 U/l), total protein S:Ag (1.15 vs 0.91 U/l), and antithrombin III activity (1.17 vs 1.08 U/l) were significantly elevated. Levels of free protein S were not different from control values. No significant decline of coagulation parameters could be recorded during insulin therapy. Patients with diabetic vasculopathy had higher levels of D-dimer than those without (133 vs 76 micrograms/l before, 109 vs 88 micrograms/l during therapy), whereas the other haemostatic parameters were not different. Our data indicate a significant activation of the coagulation system in diabetic patients with secondary failure to sulfonylurea drugs, with signs of a prethrombotic state and endothelial cell disturbance.(ABSTRACT TRUNCATED AT 250 WORDS)