Risk of adverse effects of intensified treatment in insulin-dependent diabetes mellitus: a meta-analysis

While the benefits of intensified insulin treatment in insulin-dependent (Type 1) diabetes mellitus (IDDM) are well recognized, the risks have not been comprehensively characterized. We examined the risk of severe hypoglycaemia, ketoacidosis, and death in a meta-analysis of randomized controlled trials. The MEDLINE database, reference lists, and specialist journals were searched electronically or by hand to identify relevant studies with at least 6 months of follow-up and the monitoring of glycaemia by glycosylated haemoglobin measurements. Logistic regression was used for calculation of combined odds ratios and 95% confidence intervals (95% CI). The influence of covariates was examined by including covariate-by-treatment interaction terms. Methodological study quality was assessed and sensitivity analyses were performed. Fourteen trials were identified. These contributed 16 comparisons with 1028 patients allocated to intensified and 1039 allocated to conventional treatment. A total of 846 patients suffered at least one episode of severe hypoglycaemia, 175 patients experienced ketoacidosis and 26 patients died. The combined odds ratio (95% CI) for hypoglycaemia was 2.99 (2.45-3.64), for ketoacidosis 1.74 (1.27-2.38) and for death from all causes 1.40 (0.65-3.01). The risk of severe hypoglycaemia was determined by the degree of normalization of glycaemia achieved (p=0.005 for interaction term), with the results from the Diabetes Control and Complications Trial (DCCT) in line with the other trials. Ketoacidosis risk depended on the type of intensified treatment used. Odds ratios (95% CI) were 7.20 (2.95-17.58) for exclusive use of pumps, 1.13 (0.15-8.35) for multiple daily injections and 1.28 (0.90-1.83) for trials offering a choice between the two (p = 0.004 for interaction). Mortality was significantly (p = 0.007) increased for causes potentially associated with acute complications (7 vs 0 deaths, 5 deaths attributed to ketoacidosis, and 2 sudden deaths), and non-significantly (p = 0.16) decreased for macrovascular causes (3 vs 8 deaths). We conclude that there is a substantial risk of severe adverse effects associated with intensified insulin treatment. Mortality from acute metabolic causes is increased; however, this is largely counterbalanced by a reduction in cardiovascular mortality. The excess of severe hypoglycemia in the DCCT is not exceptional. Multiple daily injection schemes may be safer than treatment with insulin pumps.

Persistent microalbuminuria in adolescents with type I (insulin-dependent) diabetes mellitus is associated to early rather than late puberty. Results of a prospective longitudinal study

Microalbuminuria is generally accepted to be highly predictive of overt diabetic nephropathy which is the leading cause of end-stage renal failure and, consequently, of death in patients with type 1 (insulin-dependent) diabetes mellitus (IDDM). Its early identification and therapy are exceedingly important. We studied prospectively the occurrence of microalbuminuria (MA) in relation to puberty and its pubertal stages in 164 children and adolescent patients (83 girls and 81 boys) with IDDM. Analysing 100 healthy subjects, normal values for albumin excretion (range: 0-10.1 micrograms/min/1.73 m2) according to sex and the different pubertal stages were defined. No significant difference between the groups were noted and, therefore, 20 micrograms/min per 1.73 m2 (3 SD above the mean) was generally defined as cutoff for MA. Of the patients with IDDM studied, 20% (20 females and 12 males) developed persistent MA (22.1-448.2 micrograms/min/1.73 m2) during the study period of 8 years. The first manifestation of persistent MA was in 69% (13 females and 9 males) during stages of early and midpuberty; and in 28% (6 females and 3 males) at a late pubertal stage or at the end of puberty. The only child who developed MA before the onset of puberty (range: 23.5-157.4 micrograms/min/1.73 m2) was found to have dystopic kidney. Therefore, all patients with IDDM should be screened for MA regardless of diabetes duration, sex and level of diabetes control beginning at the very first stage of puberty and neither earlier nor after puberty as suggested by the American Diabetes Association.

Streptozotocin-induced diabetes mellitus in pigs

We induced, as a precondition for a pancreas transplant, insulin-dependent diabetes mellitus in 67 Yorkshire Landrace pigs by administering streptozotocin. A dosage of 150 mg/kg body weight gave rise to a long-lasting diabetes mellitus that persisted with time (follow-up period: 26 weeks). Consecutive measurements of serum glucose and plasma insulin, before and up to 30 hours after administering streptozotocin, revealed triphasic behavior: initial hyperglycemia (1st to 3rd hour), pronounced hypoglycemia (12th to 18th hour), then hyperglycemia (22nd hour on). IVGTTs done 1 to 7 days after administering streptozotocin revealed a reduction of the K-value (glucose disappearance rate) from 0.3 (day 2) to 0.07 (day 4). Immunohistochemical studies revealed a complete loss of all beta-cells, concomitantly with a relative increase in glucagon- and somatostatin-positive cells. We also observed a complete loss of pp (pancreatic polypeptide)-positive cells. Diabetes induced by streptozotocin at 150 mg/kg body weight is complete and permanent; our mortality rate was 0%. Given the high morbidity rate after pancreatectomy, streptozotocin should be the method of choice for inducing diabetes mellitus in pigs.

[Will type I diabetes mellitus be treated with immunosuppressive drugs in the future?]

Even if the pathogenesis of type-I (insulin-dependent) diabetes mellitus is still not clarified in every detail, there is general agreement that this form of diabetes is induced by autoimmune mechanisms leading to beta-cell destruction. Therefore, it should theoretically be feasible to suppress the mechanism leading to type-I diabetes with appropriate and early immunotherapy. The current clinical data clearly document that the rate and duration of remissions in patients with newly diagnosed type-I diabetes can be increased significantly using appropriate immunosuppressive regimens. However, before these therapies can become standard therapy of type-I diabetes, the following important clinical requirements have to be fulfilled: the toxicity (especially to kidneys and beta-cells) has to be reduced, the patients should be diagnosed and treated in 'pre-diabetic' states, more selective immunosuppressive regimens have to be available in order to reduce the occurrence of treatment-associated lymphomas and neoplasias. Since accurate detection of 'pre-diabetic' patients is difficult and presents an immense logistic problem, it may take a long time before large-scale immunosuppressive therapies of type-I diabetes are feasible.

[Pancreas transplantation as treatment of diabetes mellitus]

Pancreatic transplantation is able to normalize blood glucose metabolism and achieve normoglycemia in a majority of patients with insulin-dependent diabetes mellitus. Hoping that normoglycemia will favorably influence development of late complications of diabetes, an increasing number of pancreas transplantations has been performed over the last years. However, the need for immunosuppressive therapy with its problems and possible complications confines pancreatic transplantation mainly to three groups of patients: patients who undergo kidney transplantation for diabetic nephropathy, patients who have already undergone kidney transplantation for diabetic nephropathy and, rarely, patients with extreme difficulties with metabolic control. The results of pancreatic transplantation have continuously improved over the last decade, and a limited number of controlled studies is providing some evidence of a favorable effect on late complications.

The effect of growth hormone (GH) replacement therapy in adult patients with type 1 diabetes mellitus and GH deficiency

Specific problems in patients with insulin-dependent diabetes mellitus (IDDM) and GH deficiency are hypoglycaemic attacks, increased insulin sensitivity and loss of energy. These problems may be related to GH deficiency.

Insulin increases serum leptin concentrations in children and adolescents with newly diagnosed type I diabetes mellitus with and without ketoacidosis.

AIMS/HYPOTHESIS The aims of this study were to analyse the changes of serum leptin in newly diagnosed children and adolescents with Type I (insulin-dependent) diabetes mellitus after insulin treatment and to examine the possible impact of ketoacidosis on these changes. METHODS Baseline serum leptin concentrations were measured in 28 newly diagnosed Type I diabetic patients [age 8.75 +/- 4.05 years (means +/- SD); BMI 15.79 +/- 2.47 kg/m(2); HbA(1 c) 11.3 +/- 1.9 %] with (n = 18) and without (n = 10) ketoacidosis before commencement of insulin treatment, at the time of diagnosis. Thereafter, during a 4-day course of continuous intravenous insulin injection to gain and maintain euglycaemia, serum leptin concentrations were assessed. RESULTS Baseline serum leptin concentrations, adjusted to age, BMI, sex and pubertal stage, differed among these patients. There was, however, an increase of leptin in all subjects from 1.37 +/- 0.56 ng/ml (mean +/- SD) up to 2.97 +/- 1.52 ng/ml by 117 % (p < 0.0001) after insulin therapy. On average, peak serum leptin concentration was obtained after 42 h of insulin treatment. Further, there was no difference in the mean increase of serum leptin concentrations in the two groups, namely with and without ketoadicosis, of insulin-dependent diabetic children and adolescents. In addition, there was no correlation between serum leptin concentrations and correction of ketoacidosis during insulin treatment. CONCLUSIONS/INTERPRETATION Insulin increases serum leptin, within 1 day, in children and adolescents with newly diagnosed Type I diabetes. Ketoacidosis does not influence this interaction between insulin and leptin.

Metabolomics reveals attenuation of the SLC6A20 kidney transporter in nonhuman primate and mouse models of type 2 diabetes mellitus

To enhance understanding of the metabolic indicators of type 2 diabetes mellitus (T2DM) disease pathogenesis and progression, the urinary metabolomes of well characterized rhesus macaques (normal or spontaneously and naturally diabetic) were examined. High-resolution ultra-performance liquid chromatography coupled with the accurate mass determination of time-of-flight mass spectrometry was used to analyze spot urine samples from normal (n = 10) and T2DM (n = 11) male monkeys. The machine-learning algorithm random forests classified urine samples as either from normal or T2DM monkeys. The metabolites important for developing the classifier were further examined for their biological significance. Random forests models had a misclassification error of less than 5%. Metabolites were identified based on accurate masses (<10 ppm) and confirmed by tandem mass spectrometry of authentic compounds. Urinary compounds significantly increased (p < 0.05) in the T2DM when compared with the normal group included glycine betaine (9-fold), citric acid (2.8-fold), kynurenic acid (1.8-fold), glucose (68-fold), and pipecolic acid (6.5-fold). When compared with the conventional definition of T2DM, the metabolites were also useful in defining the T2DM condition, and the urinary elevations in glycine betaine and pipecolic acid (as well as proline) indicated defective re-absorption in the kidney proximal tubules by SLC6A20, a Na(+)-dependent transporter. The mRNA levels of SLC6A20 were significantly reduced in the kidneys of monkeys with T2DM. These observations were validated in the db/db mouse model of T2DM. This study provides convincing evidence of the power of metabolomics for identifying functional changes at many levels in the omics pipeline.

Microalbuminuria in diabetes mellitus: efficacy of a new screening method in comparison with timed overnight urine collection

Diabetic nephropathy and end-stage renal failure are still a major cause of mortality amongst patients with diabetes mellitus (DM). In this study, we evaluated the Clinitek-Microalbumin (CM) screening test strip for the detection of microalbuminuria (MA) in a random morning spot urine in comparison with the quantitative assessment of albuminuria in the timed overnight urine collection ("gold standard"). One hundred thirty-four children, adolescents, and young adults with insulin-dependent DM Type 1 were studied at 222 outpatient visits. Because of urinary tract infection and/or haematuria, the data of 13 visits were excluded. Finally, 165 timed overnight urine were collected in the remaining 209 visits (79% sample per visit rate). Ten (6.1%) patients presented MA of > or =15 microg/min. In comparison however, 200 spot urine could be screened (96% sample/visit rate) yielding a significant increase in compliance and screening rate (P<.001, McNemar test). Furthermore, at 156 occasions, the gold standard and CM could be directly compared. The sensitivity and the specificity for CM in the spot urine (cut-off > or =30 mg albumin/l) were 0.89 [95% confidence interval (CI) 0.56-0.99] and 0.73 (CI 0.66-0.80), respectively. The positive and negative predictive value were 0.17 (CI 0.08-0.30) and 0.99 (CI 0.95-1.00), respectively. Considering CM albumin-to-creatinine ratio, the results were poorer than with the albumin concentration alone. Using CM instead of quantitative assessment of albuminuria is not cost-effective (35 US dollars versus 60 US dollars/patient/year). In conclusion, to exclude MA, the CM used in the random spot urine is reliable and easy to handle, but positive screening results of > or =30 mg albumin/l must be confirmed by analyses in the timed overnight collected urine. Although the screening compliance is improved, in terms of analysing random morning spot urine for MA, we cannot recommend CM in a paediatric diabetic outpatient setting because the specificity is far too low.

Exercise-induced growth hormone response in euglycaemia and hyperglycaemia in patients with Type 1 diabetes mellitus

To compare exercise-induced growth hormone (GH) response in patients with Type 1 diabetes during stable euglycaemic and hyperglycaemic conditions.

Response of interleukin-6 during euglycaemic and hyperglycaemic exercise in patients with type 1 diabetes mellitus

The aim of this randomized, single-blinded cross-over study was to investigate the response of interleukin-6 (IL-6) during moderate aerobic exercise in stable euglycaemia and hyperglycaemia in seven male patients with type 1 diabetes mellitus. IL-6 increased significantly over the entire study period in euglycaemia, but not in hyperglycaemia.

Pro-inflammatory biomarkers during experimental gingivitis in patients with type 1 diabetes mellitus: a proof-of-concept study

To compare gingival crevicular fluid (GCF) biomarker levels and microbial distribution in plaque biofilm (SP) samples for subjects with type 1 diabetes (T1DM) versus healthy subjects without diabetes during experimental gingivitis (EG).

Expression of adipokines and estrogen receptors in adipose tissue and placenta of patients with gestational diabetes mellitus

The purpose of this study was to assess the expression profile of genes with potential role in the development of insulin resistance (adipokines, cytokines/chemokines, estrogen receptors) in subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and placenta of pregnant women with gestational diabetes mellitus (GDM) and age-matched women with physiological pregnancy at the time of Caesarean section. qRT-PCR was used for expression analysis of the studied genes. Leptin gene expression in VAT of GDM group was significantly higher relative to control group. Gene expressions of interleukin-6 and interleukin-8 were significantly increased, whereas the expressions of genes for estrogen receptors alpha and beta were significantly reduced in SAT of GDM group relative to controls, respectively. We found no significant differences in the expression of any genes of interest (LEP, RETN, ADIPOR1, ADIPOR2, TNF-alpha, CD68, IL-6, IL-8, ER alpha, ER beta) in placentas of women with GDM relative to controls. We conclude that increased expression of leptin in visceral adipose depot together with increased expressions of proinflammatory cytokines and reduced expressions of estrogen receptors in subcutaneous fat may play a role in the etiopathogenesis of GDM.

Impact of single nucleotide polymorphisms and of clinical risk factors on new-onset diabetes mellitus in HIV-infected individuals

Background. Metabolic complications, including cardiovascular events and diabetes mellitus (DM), are a major long-term concern in human immunodeficienc virus (HIV)-infected individuals. Recent genome-wide association studies have reliably associated multiple single nucleotide polymorphisms (SNPs) to DM in the general population. Methods. We evaluated the contribution of 22 SNPs identifie in genome-wide association studies and of longitudinally measured clinical factors to DM. We genotyped all 94 white participants in the Swiss HIV Cohort Study who developed DM from 1 January 1999 through 31 August 2009 and 550 participants without DM. Analyses were based on 6054 person-years of follow-up and 13,922 measurements of plasma glucose. Results. The contribution to DM risk explained by SNPs (14% of DM variability) was larger than the contribution to DM risk explained by current or cumulative exposure to different antiretroviral therapy combinations (3% of DM variability). Participants with the most unfavorable genetic score (representing 12% and 19% of the study population, respectively, when applying 2 different genetic scores) had incidence rate ratios for DM of 3.80 (95% confidenc interval [CI], 2.05–7.06) and 2.74 (95% CI, 1.53–4.88), respectively, compared with participants with a favorable genetic score. However, addition of genetic data to clinical risk factors that included body mass index only slightly improved DM prediction. Conclusions. In white HIV-infected persons treated with antiretroviral therapy, the DM effect of genetic variants was larger than the potential toxic effects of antiretroviral therapy. SNPs contributed significantl to DM risk, but their addition to a clinical model improved DM prediction only slightly, similar to studies in the general population.

Health risk appraisal for older people 4: case finding for hypertension, hyperlipidaemia and diabetes mellitus in older people in English general practice before the introduction of the Quality and Outcomes Framework

Early intervention can help to reduce the burden of disability in the older population, but many do not access preventive care. There is uncertainty over what factors influence case finding in older patients in general practice.