Sex-matched Nondiabetic Control Subjects Research Articles

Bacterial infections in patients with type 1 diabetes: a 14-year follow-up study

ObjectiveThis study explored the annual occurrence/incidence of bacterial infections, and their association with chronic hyperglycemia and diabetic nephropathy, in patients with type 1 diabetes.DesignIn a register-based follow-up study, we investigated...

Trabecular bone histomorphometry in humans with Type 1 Diabetes Mellitus.

Patients with Type 1 Diabetes Mellitus (DM) have markedly increased risk of fracture, but little is known about abnormalities in bone microarchitecture or remodeling properties that might give insight into the pathogenesis of skeletal fragility in these patients. We report here a case-control study comparing bone histomorphometric and micro-CT results from iliac biopsies in 18 otherwise healthy subjects with Type 1 Diabetes Mellitus with those from healthy age- and sex-matched non-diabetic control subjects. Five of the diabetics had histories of low-trauma fracture. Transilial bone biopsies were obtained after tetracycline labeling. The biopsy specimens were fixed, embedded, and scanned using a desktop μCT at 16 μm resolution. They were then sectioned and quantitative histomorphometry was performed as previously described by Recker et al. [1]. Two sections, >250 μm apart, were read from the central part of each biopsy. Overall there were no significant differences between diabetics and controls in histomorphometric or micro-CT measurements. However, fracturing diabetics had structural and dynamic trends different from nonfracturing diabetics by both methods of analysis. In conclusion, Type 1 Diabetes Mellitus does not result in abnormalities in bone histomorphometric or micro-CT variables in the absence of manifest complications from the diabetes. However, diabetics suffering fractures may have defects in their skeletal microarchitecture that may underlie the presence of excess skeletal fragility.

Risk of Newly Diagnosed Type 2 Diabetes Is Reduced in Users of Alendronate

To study the risk of developing type 1 (T1D) or type 2 (T2D) diabetes among users of drugs against osteoporosis compared to nonusers. Nationwide cohort study in Denmark with all users of drugs against osteoporosis (n=103,562) as exposed and three age- and sex-matched nondiabetic control subjects (n=310,683) randomly selected from the background population. The main outcome variable was an incident diagnosis of diabetes after the baseline date. Among users of alendronate, etidronate, and raloxifene, no change in the risk of T1D was observed. However, the risk of developing T2D was reduced with all three drugs (alendronate: hazard ratio [HR]=0.71, 95% confidence interval [CI] 0.59-0.85, etidronate: HR=0.77, 95% CI 0.69-0.86, raloxifene: HR=0.46, 95% CI 0.25-0.87). For alendronate, a dose-dependent risk reduction was observed (≥1 defined daily dose (DDD) per day: HR=0.22, 95% CI 0.12-0.41, P for trend<0.01), while this was not the case for etidronate and raloxifene. Antiresorptive drugs do not seem associated with an increased risk of diabetes, but they may perhaps provide a protective effect related to the suppression of bone turnover. However, further studies are needed.

Elevation of soluble form of receptor for advanced glycation end products (sRAGE) in diabetic subjects with coronary artery disease

Advanced glycation end products (AGEs)-receptor (RAGE) axis is implicated in diabetic vascular complication. Since a soluble form of RAGE (sRAGE) could be generated from the cleavage of cell surface RAGE in endothelial cells (ECs), serum sRAGE levels may be elevated in diabetes consequent to EC damage. In this study, we examined whether sRAGE levels were elevated in type 2 diabetic patients compared with non-diabetic healthy subjects. Serum sRAGE levels were examined in 75 Japanese type 2 diabetic patients (29 men and 46 women; mean age 66 +/- 11 years) and 75 age- and sex-matched non-diabetic healthy control subjects. We explored the association between sRAGE levels and coronary artery disease (CAD) in diabetic patients. Serum sRAGE levels were significantly higher in diabetic patients than in non-diabetic subjects (965.3 +/- 544.2 vs 415 +/- 150.4 pg/mL, p < 0.001). In the univariate analysis, diastolic blood pressure (inversely), LDL cholesterol, triglycerides, HDL cholesterol, hemoglobin A(1c), and creatinine were significantly associated with sRAGE. After performing multivariate analyses, the presence of diabetes (p < 0.0001) was a sole independent determinant of sRAGE. Furthermore, there was a significant difference in sRAGE levels between diabetic patients with CAD and those without CAD (1680.6 +/- 891.1 vs 855.2 +/- 372.1 pg/mL, p < 0.001). Multiple stepwise regression analysis revealed that sRAGE and creatinine levels were independent determinants of CAD. The present study demonstrated that serum sRAGE levels were significantly higher in type 2 diabetic patients than in non-diabetic subjects and positively associated with the presence of CAD.

The cost burden of diabetes mellitus: the evidence from Germany—the CoDiM Study

The aim of this study was to identify the health care costs of diabetic patients in Germany in 2001, focusing on the influence of age, sex, and type of treatment. Annual direct costs of medical care and indirect costs of inability to work and early retirement in diabetic subjects were compared with costs of age- and sex-matched non-diabetic control subjects. The analysis was based on routine health care data from a random sample (18.75%) taken from a database of 1.9 million insured persons. Incremental differences in medical and national expenditure between subjects with and without diabetes were calculated. Annual direct mean costs per diabetic patient were 5,262 Euro, and indirect costs were 5,019 Euro. In the control group, mean direct and indirect costs were 2,755 Euro and 3,691 Euro, respectively. Analysis of cost components revealed that the high costs associated with the care of diabetic patients could be largely attributed to inpatient care and overall medication costs. Hypoglycaemic drugs amounted to only one-quarter of the medication costs. The total health care costs were correlated with the type of treatment. Direct excess costs increased with increasing age in insulin-treated patients, but were unaffected by age in patients receiving other types of treatment. The Costs of Diabetes Mellitus (CoDiM) study is the first comprehensive study to provide estimates of costs associated with diabetes care in Germany. Direct costs of diabetic patients account for 14.2% of total health care costs, which includes the proportion that specifically accounts for diabetes-related costs (6.8%).

Relative Risk of Mortality Associated With Diabetes as a Function of Birth Weight

Birth weight is a risk factor for both diabetes and mortality. Diabetes is a risk factor for mortality. Whether the excess mortality observed for diabetes varies with birth weight is unclear. Among all 2,508 Rochester, Minnesota, residents who first met research criteria for adult-onset diabetes in 1960-1995, 171 were born locally in-hospital after 1922 (i.e., birth weights available) as singleton, term infants. Each case subject and two age- and sex-matched nondiabetic control subjects (born locally, residing locally when the case subject met the criteria for diabetes) were followed through 31 December 2000 for vital status. Of the diabetic case subjects, 16% (27 of 171) died vs. 7% (25 of 342) of control subjects (P = 0.004). The difference was less for normal-birth-weight (NBW) (2,948-<3,856 g) individuals (12% [12 of 102] vs. 8% [20 of 246], P = 0.31) than for abnormal-birth-weight individuals (low birth weight [LBW] 20% [8 of 39] vs. 2% [1 of 46], P = 0.01; high birth weight [HBW] 23% [7 of 30] vs. 8% [4 of 50], P = 0.16), as confirmed with age- and sex-adjusted Cox proportional hazards (diabetes-associated hazard ratio 1.4 [95% CI 0.69-2.90] for NBW vs. 4.8 [1.7-13.3] for abnormal birth weight, test for interaction P = 0.056). The observed diabetes deaths were greater than expected, based on mortality for the general population (27 vs. 13.3, P < 0.001), with 70% of excess deaths occurring among LBW (8 vs. 2.2, P < 0.001) and HBW (7 vs. 3.1, P = 0.03) individuals. The excess mortality observed for diabetes appears disproportionately concentrated among abnormal-birth-weight individuals, thus identifying a subset of at-risk diabetic individuals and reinforcing the importance of NBW deliveries.

Increased CD40 ligand and platelet–monocyte aggregates in patients with type 1 diabetes mellitus

Background: Diabetes mellitus is a major risk factor for cardiovascular disease and is associated with a proinflammatory and prothrombotic state. We investigated whether CD40 ligand (L) expression and platelet–monocyte aggregation are increased in patients with type 1 diabetes. Methods: Serum C-reactive protein (CRP) and soluble (s) CD40L concentrations, platelet surface CD40L expression and platelet–monocyte aggregates were measured in 22 patients with uncomplicated type 1 diabetes and 22 age- and sex-matched non-diabetic control subjects. Results: In comparison to controls, patients with type 1 diabetes had higher serum CRP concentrations (3.29 ± 0.9 mg/L versus 0.99 ± 0.2 mg/L, P = 0.01), serum sCD40L concentrations (10.0 ± 1.4 ng/mL versus 4.6 ± 0.6 ng/mL, P = 0.006), and platelet surface expression of CD40L (13.8 ± 0.9% versus 8.5 ± 1.1%, P < 0.001). Platelet–monocyte aggregates were also significantly elevated in type 1 diabetes (35.9 ± 3.3% versus 26.4 ± 2.9%, P = 0.005; n = 10). We also observed a significant correlation between plasma glucose and serum CRP ( r = 0.53, P = 0.01) as well as platelet–monocyte aggregates ( r = 0.69, P = 0.03). Conclusions: Type 1 diabetes is associated with increased CD40L expression and platelet–monocyte aggregation, which may contribute to the proinflammatory and prothrombotic state as well as the accelerated atherogenesis associated with this disorder.

Comparison of carotid intima-media thickness, arterial stiffness, and brachial artery flow mediated dilatation in diabetic and nondiabetic subjects (The Chennai Urban Population Study [CUPS-9

This study compares flow-mediated dilation (FMD) and the augmentation index (AI) in diabetic and nondiabetic subjects and correlates these measurements with carotid intima-media thickness (IMT). Fifty diabetic subjects and 50 age- and sex-matched nondiabetic control subjects were recruited from the Chennai Urban Population Study. IMT of the common carotid artery and FMD of the brachial artery were determined using high-resolution B-mode ultrasonography. AI was measured using the Sphygmocor apparatus. The mean AI of diabetic subjects was significantly higher than the nondiabetic subjects (27.48 ± 7.41% vs 19.10 ± 8.19%, p <0.0001). The FMD values were significantly lower among diabetic subjects compared with the nondiabetic subjects (2.1 ± 2.95% vs 6.64 ± 4.38%, p <0.0001). At any given age point, diabetic subjects had significantly higher AI and lower FMD values compared with nondiabetic subjects (p <0.05). In the total population, AI and FMD showed a correlation with age (p <0.001), fasting plasma glucose (p <0.01), glycosylated hemoglobin (p = 0.001), and IMT (p = 0.001). Among the nondiabetic subjects, FMD and AI showed a strong correlation with IMT. FMD also showed a strong correlation with age and systolic blood pressure, whereas AI showed a correlation with fasting plasma glucose in diabetic subjects. AI and FMD values showed a strong correlation with age. AI values increased and FMD values decreased with an increase in quartiles of IMT both in diabetic and nondiabetic subjects. Multivariate linear regression analyses in the total study population showed that age and glycosylated hemoglobin were the risk factors associated with AI and FMD, in addition to diastolic blood pressure with AI. Diabetic patients have decreased FMD and increased arterial stiffness compared with age- and sex-matched nondiabetic subjects. These functional changes correlate well with the structural changes of the arteries measured by IMT.

Early Identification of Hearing Impairment in Patients With Type 1 Diabetes Mellitus

The aim of this study was to evaluate the cochlear micromechanics and central auditory function in patients with type I diabetes mellitus and to identify the site of possible dysfunction. Cochlear activity was evaluated by recording distortion product otoacoustic emissions (DPOAEs). DPOAEs were performed using an ILO 92 Otodynamics Analyser. Functional changes in the retrocochlear auditory pathway were evaluated by auditory brainstem responses (ABRs). DPOAEs and ABRs were measured in 42 normally hearing patients with type 1 diabetes mellitus aged 21 to 42 years, and 33 age- and sex-matched nondiabetic control subjects. Both of the groups (diabetic and control) had normal and undifferentiated results in tonal and impedance audiometry. ABR peripheral transmission time (wave I) and central transmission time (interpeak latencies I-V) were significantly delayed in the diabetic compared with normal subjects, and the mean amplitudes of various DPOAEs were significantly reduced in the diabetic patients compared with the control subjects. Combined use of different procedures for monitoring central and peripheral portions of the auditory pathway in diabetic patients showed alterations in cochlear micromechanics and the retrocochlear auditory pathway. Hearing impairment in diabetic patients is usually mild and subclinical, and can be detected early by accurate and objective audiometric methods.

Cochlear dysfunction and diabetic microangiopathy.

The aim of this study was to evaluate the cochlear micromechanics in type 1 diabetic patients and to compare these findings with diabetic microvascular complications (retinopathy and nephropathy). Cochlear activity was evaluated by recording 2f1-f2 DPOAE. DPOAEs were performed using an ILO92 Otodynamics Ltd Analyser. DPOAEs were measured in 42 normally hearing IDDM patients aged between 21 and 42 years, and 33 age-and sex-matched non-diabetic control subjects. IDDM patients were divided into two groups: 17 patients without microangiopathy and 25 with microangiopathy. Microangiopathy was evaluated with ophthalmoscopy and 24-hour albumin excretion rate into urine. Both groups (diabetic and control) had normal and undifferentiated results in tonal and impedance audiometry. The mean amplitudes of various DPOAEs were significantly reduced in the diabetic groups (with and without microangiopathy) compared with control subjects. No correlation was found between diabetic microvascular complications and DPOAE amplitudes reduction. Our results indicate the existence of an alteration in cochlear micromechanics in diabetic patients with microangiopathy as well as in patients without microangiopathy. The lack of significant correlation between the degree of microvascular complications in the retina or kidneys and DPOAEs amplitude reduction suggest that the impaired functional properties of the outer hair cells are probably caused by early metabolic complications in diabetes (among other things non-enzymatic glycation related to hyperactivity of free oxygen radicals) and not directly by diabetic microangiopathy.

Ambulatory blood pressure, microalbuminuria, and autonomic neuropathy in adolescents with type 1 diabetes.

To examine the relationship between 24-h blood pressure (BP) measurements, urinary albumin excretion rates, and autonomic neuropathy (AN) in adolescents with type 1 diabetes. A total of 31 patients with microalbuminuria (MA), 20 patients with intermittent MA (I-MA) and 11 patients with persistent MA (P-MA) were identified from the diabetes clinics at two major Australian tertiary care pediatric hospitals. Two control groups were used; one consisted of 19 age-, sex-, and diabetes duration-matched adolescents with normoalbuminuria (NA), and the other consisted of 46 age- and sex-matched nondiabetic control subjects. A medical history and physical examination were followed by a series of noninvasive tests of cardiovascular and pupillary autonomic function and then by 24-h ambulatory blood pressure monitoring (ABPM). ABPM showed an incremental increase in all BP parameters from nondiabetic control subjects through subjects with NA. A parallel incremental increase in diurnal and nocturnal ambulatory heart rates was also evident. Subjects with MA had significantly reduced pupillary adaptation to darkness compared with nondiabetic subjects and subjects with NA. The above results paralleled an incremental increase in HbAlc levels in adolescents with type 1 diabetes from subjects with NA to subjects with P-MA. Higher 24-h BP values and evidence of subclinical signs of AN are present before P-MA develops and may have important implications for timing the introduction of treatments designed to prevent or retard the microvascular complications of type 1 diabetes in adolescents.

Increased cytosolic free sodium concentrations in platelets from type 2 (non-insulin-dependent) diabetic patients is associated with hypertension

Cytosolic free sodium concentrations ([Na+]i) in intact platelets from 32 type 2 (non-insulin-dependent) diabetic patients and from 27 age- and sex-matched non-diabetic control subjects were measured with the novel sodium-sensitive fluorescent dye sodium-binding-benzofuran-isophthalate. [Na+]i was significantly higher in platelets from type 2 diabetic patients compared with control subjects (40.6 +/- 2.4 vs 32.0 +/- 2.0 mmol/l, means +/- S.E.M., P < 0.03). Both systolic and diastolic blood pressure were significantly elevated in diabetic patients compared with control subjects. Analysis of diabetic patients showed a significant association between [Na+]i and diastolic blood pressure (P = 0.026). Stimulation of Na/H exchange by thrombin increased [Na+]i in both groups. After inhibition of Na/K/ATPase by ouabain (1 mmol/l), [Na+]i was significantly increased both in diabetic patients and non-diabetic subjects in a similar way (by 40.2 +/- 7.3 and 31.7 +/- 5.3 mmol/l respectively). It is concluded that increased [Na+]i in cells from type 2 diabetic patients may be related to hypertension.

Eating disorders in adolescents with IDDM. A controlled study.

To determine the prevalence of clinical eating disorders and lesser degrees of disturbed eating in adolescents with IDDM and a matched sample of nondiabetic control subjects. A cross-sectional survey of eating habits and attitudes conducted in 76 adolescents with IDDM, and age- and sex-matched nondiabetic control subjects. Eating disorder features were assessed by standardized research interview adapted for use with patients with diabetes (EDE). Glycemic control was assessed by GHb assay. Adolescent girls with IDDM were heavier than nondiabetic female control subjects and were dieting more intensively to control their shape and weight. However, clinical eating disorders were no more common among adolescent girls with IDDM than among nondiabetic control subjects. Nine percent of the IDDM girls met diagnostic criteria for an operational version of "Eating disorder not otherwise specified." Fifteen percent had omitted or reduced their dose of insulin to influence their shape and weight. Eating disorder features and insulin misuse for shape and weight control were not found in IDDM or nondiabetic boys, and these two groups did not differ in their body weight. Adolescent girls with IDDM are heavier than their nondiabetic counterparts and diet more intensively to control their shape and weight. Disordered eating habits and weight control behavior are common, but no more so in IDDM than in nondiabetic subjects. Insulin misuse for the purpose of shape and weight control is not restricted to subjects with a clinical eating disorder. Disordered eating is associated with impaired glycemic control.

Erythrocyte insulin binding abnormalities in fibro calculous pancreatic diabetes.

Insulin binding to erythrocyte insulin receptors was studied in 17 patients (13 men and 4 women) with fibrocalculous pancreatic diabetes mellitus (FCPD) and compared with that of 14 newly diagnosed NIDDM patients matched for age, sex and severity of hyperglycemia, and 14 age and sex-matched non-diabetic control subjects. In the uncompensated diabetic state, mean (+/- S.D.) specific binding of insulin was lower in both FCPD and NIDDM patients, compared with non-diabetic controls (P less than 0.001). Control of diabetes with short term therapy (2-6 weeks) resulted in a significant improvement in the mean specific insulin binding in both FCPD and NIDDM patients (P less than 0.001) due to increased binding affinity in the former, and increased affinity and the number of binding sites in the latter. As compared to short term therapy, chronic therapy (5-8 months) in FCPD patients resulted in a marginal decrease in specific insulin binding. However, this was still significantly higher than the basal value (P less than 0.05). FCPD patients had an initial low mean basal plasma IRI and a much lower mean stimulated IRI response as compared to NIDDM and non-diabetic controls.

Benign migratory glossitis in patients with juvenile diabetes

The prevalence of tissue type HLA-B15 has been shown to be higher in atopic patients with benign migratory glossitis and in patients with insulin-dependent diabetes mellitus than it is in the general population. Despite this apparent link, the possible relationship between benign migratory glossitis and insulin-dependent diabetes mellitus does not appear to have been investigated previously. This study of 87 diabetic patients and 105 age- and sex-matched nondiabetic control subjects revealed a fourfold increase in the prevalence of benign migratory glossitis in the diabetic group. These results suggest that benign migratory glossitis may be linked to diabetes mellitus and that further investigation of this association is warranted.

Infection and Diabetes: The Case for Glucose Control

This review summarizes data concerning the host resistance to infection in diabetes and the influence of an acute infection upon the endocrinologic-metabolite status of the diabetic patient. While it is well known that acute infections lead to difficulty in controlling blood sugar levels and the infection is the most frequently documented cause of ketoacidosis, controversy persists as to whether or not patients with diabetes mellitus are more susceptible to infection than age- and sex-matched nondiabetic control subjects. Our data obtained from the charts of 241 diabetic patients who were being followed as outpatients show a striking direct correlation between the overall prevalence of infection (p less than 0.001) and the mean plasma glucose levels (representing three or more fasting glucose determinations taken at times when no evidence of infection existed). There is a significant diminution in intracellular bactericidal activity of leukocytes with Staphylococcus aureus and Escherichia coli in subjects with poorly controlled diabetes in comparison with the control group. Serum opsonic activity for both Staph. Aureus and E. coli were significantly lower than in the control subjects. Taken together, the results from published reports as well as our data suggest to us that good control of blood sugar in diabetic patients is a desirable goal in the prevention of certain infections (Candida vaginitis, for example) and to ensure maintenance of normal host defense mechanisms that determine resistance and response to infection.

Postheparin Plasma Lipoprotein Lipase and Hepatic Lipase in Diabetes Mellitus: Relationship to Plasma Triglyceride Metabolism

The activity of two triglyceride lipases was determined by an immunochemical method in the postheparin plasma of 60 diabetic patients and of 47 age- and sex-matched nondiabetic control subjects. The results were related to the type of diabetes, to plasma triglyceride and insulin concentrations, to removal of exogenous fat from the blood, and to turnover of VLDL-triglycerides . The mean postheparin plasma lipoprotein lipase (LPL) activity was decreased by 44 per cent (p less than 0.001) in patients with untreated ketotic diabetes and by 20 per cent (p less than 0.01) in patients with untreated mild to moderate nonketotic early-onset diabetes. Insulin treatment of ketotic diabetes resulted in a rapid increase in the activity of LPL and decrease in serum triglycerdie level, whereas sulfonylurea treatment of non-insulin-requiring diabetics did not significantly influence the enzyme activity. In insulin-treated chronic diabetics the average postheparin plasma LPL activity was not different from that of nondiabetic controls, but some of these patients had high LPL values. In normolipidemic maturity-onset-type diabetics the LPL activity was within normal range, but in those having hypertriglyceridemia the average LPL value was decreased by an average of 26 per cent (p less than 0.01). The LPL activity showed a significant negative correlation with the logarithm of serum triglyceride concentration (r = -0.62) and a positive correlation with fractional removal of Intralipid (r = +0.64) and fractional turnover of V triglyceride (r = +0.40). The activity of LPL was correlated to basal plasma insulin concen tration in the insulin-deficient diabetes r = +0.34) but not in patients with maturity-onset-type diabetes. The hepatic lipase (HL) activity of postheparin plasma was similar in diabetes and controls, with the exception of hypertriglyceridemic maturity-onset diabetics, who had higher mean HL activity than the corresponding control group (p greater than 0.01). The activity of HL was not related to triglyceride removal but showed a significant correlation to VLDL-triglyceride production rate. On the basis of these results it seems that a deficiency of LPL accounts for a great deal of the elevation of serum triglyceride in insulin-deficient human diabetes but has a smaller role in the pathogenesis of the hypertriglyceridemia that is associated with maturity-onset diabetes. The latter abnormality is caused mainly by an increased secretion of triglycerides into the blood even though a decreased LPL may contribute to development of hyperlipemia in cases with gross elevation of serum triglycerides.