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PubMed1998

Predictors of progression from normoalbuminuria to microalbuminuria in NIDDM.

OBJECTIVE: Our objective was to establish the clinical, genetic, metabolic, and immunologic risk factors for the progression of the albumin excretion rate (AER) in normoalbuminuric NIDDM patients. RESEARCH DESIGN AND METHODS: We recruited 108 NIDDM patients with normal AER after a diabetes duration of 9 years to participate in a prospective 9-year follow-up. In addition to conventional clinical and metabolic variables, we assessed microvascular (retinopathy, nephropathy, neuropathy) and macrovascular (coronary heart disease, peripheral vascular disease) diabetic complications, genetic markers (HLA genotypes), and organ-specific autoimmune markers, including islet cell antibodies. Multiple logistic regression was used to determine independent predictors of progression of AER. RESULTS: A total of 21 patients (19%) died during the follow-up. There was an overrepresentation of men (61 vs. 39%; P = 0.044) and smokers (55 vs. 27%; P = 0.01) in patients who progressed to micro- or macroalbuminuria versus those who did not progress. In addition, progressors had higher fasting plasma glucose (P = 0.002) and HbA1 (P = 0.0002) concentrations at baseline than did nonprogressors. Neuropathy was more often seen in progressors than in nonprogressors at baseline (53 vs. 16%; P = 0.0004). Frequency of HLA genotypes and autoimmune markers did not differ between progressors and nonprogressors. In a multiple logistic regression analysis, HbA1 (P = 0.0005) and a history of smoking (P = 0.011) were independent predictors of progression of AER. CONCLUSIONS: This study reemphasizes the importance of poor glycemic control and smoking as independent risk factors for progression of AER. Furthermore, development of micro- or macroalbuminuria in NIDDM was associated with neuropathy and male sex.

Adult↗

PubMed2001

[Free radical scavenging activity of sulfonylureas: a clinical assessment of the effectiveness of gliclazide].

In long-term clinical studies the beneficial effects of gliclazide on platelets have been related to a reduction in oxidative stress. This property is because of gliclazide's free radical scavenging ability that relates to the unique amino azabicyclo-octane ring, which is grafted on to the sulfonylurea. During a blinded clinical trial, the possible effects of gliclazide were assessed in 30 non-insulin-dependent diabetic patients. All patients had been treated for diabetes for more than 2 years (mean 8 years) and had been established on glibenclamide for over 2 years with or without adjunctive metformin therapy. Patients were studied for 6 months and randomized to continue either their present dose of glibenclamide or to be converted to an equipotent dose of gliclazide. Measurements were taken of hemostatic variables, the oxidative status of the plasma, and the redox status, both extracellularly as plasma albuminthiols (PSH) and lipid peroxides, and intracellularly as red blood cell superoxide dismutase activity (SOD). At 3 months, diabetic control was unaltered, but there were significant improvements in the oxidative status of the gliclazide-treated patients. Lipid peroxides decreased (8.3 +/- 1.1 to 7.0 +/- 0.06 mumol/l, P < 0.01) and red blood cell SOD increased (135 +/- 21 to 152 +/- 36 micrograms/ml, P < 0.05). PSH levels were unaltered at 453 +/- 38 mumol/l, whereas they had decreased significantly in the glibenclamide patients (414 +/- 34 mumol/l, P < 0.05), resulting in a significant difference between the 2 treatment groups (P < 0.004). Platelet reactivity to collagen also improved in the gliclazide-treated patients, decreasing from 65.1% +/- 14% to 50.8 +/- 24% (p < 0.01). The reactivity of the platelets remained unaltered in the glibenclamide patients. At 6 months, the significant differences between the 2 treatment groups remained. Hence, gliclazide was shown in a clinical study to have free radical scavenging activity independent of glycemic control.

Adult↗

PubMed2003

Is glycosylated hemoglobin A1c a surrogate for metabolic syndrome in nondiabetic, first-degree relatives of African-American patients with type 2 diabetes?

Glycosylated hemoglobin (Hb)A1c provides a practical assessment of long-term glycemic control in patients with diabetes. However, whether HbA1c has any clinical significance in metabolic syndrome (MS) in nondiabetic subjects remains debatable. Therefore, we examined the impact of different levels of HbA1c on insulin sensitivity (Si), non-insulin-dependent glucose disposal, and blood pressure (BP), as well as lipids and lipoproteins in nondiabetic, first-degree relatives of African-American patients with type 2 diabetes. The study consisted of 219 nondiabetic, first-degree relatives (offspring and siblings) of African-American patients with type 2 diabetes. To examine the metabolic impact of HbA1c in our population, HbA1c was divided into tertiles (normal range, 3.3-6.4%). The mean HbA1c was 4.7% (range, 3.3-4.8%, n = 74) for tertile 1, 5.4% (range, 4.9-5.6%, n = 73) for tertile 2, and 5.8% (range, 5.7-6.4%, n = 72) for tertile 3. Si and glucose effectiveness (Sg) were determined by the Bergman's minimal model method. Homeostasis model assessment (HOMA)-insulin resistance and HOMA-beta-cell function were also estimated. BP, body compositional variables, and body fat distribution, as well as fasting serum lipid and lipoprotein concentrations, were determined in each subject. The mean age, body weight, body mass index, waist and hip circumference, and systolic and diastolic BPs were significantly (P < 0.02-0.001) greater in the subjects in tertile 3 than those in tertiles 1 and 2. The mean fasting serum glucose was significantly (P < 0.01) higher in tertile 3 (95.5 +/- 3.2 mg/dl) than in tertile 2 (83.0 +/- 2.7 mg/dl) and tertile 1 (78.8 +/- 1.5 mg/dl). Mean fasting serum insulin and c-peptide levels tended to be higher in tertile 3 subjects than in those in tertiles 1 and 2, but the mean differences did not reach statistical significance. The mean Si was significantly (P < 0.001) lower in the subjects in tertile 3 [1.66 +/- 0.2019 x 10(-4).min(-1)( micro U/ml)(-1)], when compared with those in tertile 1 [2.27 +/- 0.20 19 x 10(-4).min(-1)( micro U/ml)(-1)] and tertile 2 [2.61 +/- 0.19 x 10(-4).min(-1)( micro U/ml)(-1)]. The mean Sg was significantly (P < 0.02) lower in tertile 3 (1.95 +/- 0.12 x 10(-2).min(-1)), when compared with those of tertile 1 (2.27 +/- 0.10 x 10(-2).min(-1)) and tertile 2 (2.29 +/- 0.11 x 10(-2).min(-1)). In addition, the (HOMA)-insulin resistance was significantly (P < 0.01) higher in tertile 3 (3.62 +/- 0.26) than in tertile 1 (2.6 +/- 0.21) and tertile 2 (2.55 +/- 0.31) HbA1c. In contrast, HOMA-beta-cell function, was not different among tertiles 1, 2, and 3. Mean fasting serum triglycerides, cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels also were not significantly different in subjects in tertile 3, when compared with those in tertiles 1 and 2. In summary, the present study demonstrates that the upper tertile HbA1c level (tertile 3) reflects some components of MS in the nondiabetic, obese, first-degree relatives of African-Americans who are genetically predisposed to type 2 diabetes. The metabolic abnormalities in the upper tertile 3 subjects included a reduced insulin action (Si) and reduced Sg, as well as elevated systolic and diastolic BPs, but not beta-cell secretion and lipids and lipoproteins. We conclude that the upper tertile of HbA1c should be considered as a major surrogate of MS in high-risk African-Americans who are genetically predisposed to type 2 diabetes.

Adult↗

PubMed2000

Free radical scavenging activity of sulfonylureas: a clinical assessment of the effect of gliclazide.

In long-term clinical studies the beneficial effects of gliclazide on platelets have been related to a reduction in oxidative stress. This property is because of gliclazide's free radical scavenging ability that relates to the unique amino azabicyclo-octare ring, which is grafted on to the sulfonylurea. During a blinded clinical trial, the possible effects of gliclazide were assessed in 30 non-insulin-dependent diabetic patients. All patients had been treated for diabetes for more than 2 years (mean 8 years) and had been established on glibenclamide for over 2 years with or without adjunctive metformin therapy. Patients were studied for 6 months and randomized to continue either their present dose of glibenclamide or to be converted to an equipotent dose of gliclazide. Measurements were taken of hemostatic variables, the oxidative status of the plasma, and the redox status, both extracellularly as plasma albumin-thiols (PSH) and lipid peroxides, and intracellularly as red blood cell superoxide dismutase activity (SOD). At 3 months, diabetic control was unaltered, but there were significant improvements in the oxidative status of the gliclazide-treated patients. Lipid peroxides decreased (8.3 +/- 1.1 to 7.0 +/- .06 micromol/L, P < .01) and red blood cell SOD increased (135 +/- 21 to 152 +/- 36 microg/mL, P < .05). PSH levels were unaltered at 458 +/- 38 micromol/L, whereas they had decreased significantly in the glibenclamide patients (414 +/- 34 micromol/L, P < .05), resulting in a significant difference between the 2 treatment groups (P < .004). Platelet reactivity to collagen also improved in the gliclazide-treated patients, decreasing from 65.1% +/- 14% to 50.8% +/- 24% (P < .01). The reactivity of the platelets remained unaltered in the glibenclamide patients. At 6 months, the significant differences between the 2 treatment groups remained. Hence, gliclazide was shown in a clinical study to have free radical scavenging activity independent of glycemic control.

Adult↗

PubMed1997

Predictors of renal morphological changes in the early stage of microalbuminuria in adolescents with IDDM.

OBJECTIVE: To evaluate the impact of glycemic control, blood pressure, lipid levels, glomerular filtration rate (GFR), age, and duration of IDDM on the degree of structural glomerular changes in the transitional stage of microalbuminuria. RESEARCH DESIGN AND METHODS: Fifteen adolescents (seven boys and eight girls) with > 5 years of duration of IDDM and with low-grade microalbuminuria (15-30 micrograms/min) participated. Seventeen living kidney donors served as healthy control subjects. Five-year mean HbA1c; 5-year mean systolic and diastolic blood pressure; GFR, cholesterol, and triglycerides 2-5 years before renal biopsy; age; and duration of IDDM were investigated and related to basement membrane thickness (BMT), mesangial and matrix volume fractions, and the overall glomerulopathy index [(BMT/10 + mat/glom, %) + matrix star volume]. RESULTS: BMT and the overall diabetic glomerulopathy were increased in diabetic patients as compared with control subjects (P < 0.001), whereas matrix volume fraction, but not mesangial volume fraction, tended to be increased (P = 0.11). In multivariate analysis, BMT was predicted by 5-year mean HbA1c, diabetes duration, and previous GFR (R2 = 0.71, P = 0.003). With matrix volume fraction as the dependent variable, BMT and diabetes duration were the only significant determinants (R2 = 0.63, P = 0.003). Diabetes duration, 5-year mean HbA1c, and GFR were the variables with an independent influence on the overall diabetic glomerulopathy index (R2 = 0.72, P = 0.003). Preceding blood pressure and lipid levels or age had no significant independent influence on these morphometric measures. CONCLUSIONS: In the very early stage of microalbuminuria in IDDM adolescents, a high percentage of the variation in BMT and overall severity of glomerulopathy is explained by prolonged hyperglycemia and diabetes duration. Previous glomerular hyperfiltration may also add to the prediction of these morphological changes.

Adolescent↗

PubMed1987

Management of the insulin-dependent diabetic during labor and delivery. Influences on neonatal outcome.

Infants of insulin-dependent diabetic mothers are at risk for neonatal polycythemia, hyperbilirubinemia, respiratory distress syndrome (RDS), and hypoglycemia. The purpose of this study was to determine whether labor and delivery management of diabetes may influence the rate of these complications. We hypothesized a priori that: infants of diabetic mothers delivered by cesarean section have a lower rate of neonatal polycythemia and hyperbilirubinemia, but a higher rate of RDS, than infants of diabetic mothers delivered by vaginal route, and poor glycemic control during labor increases the rate of neonatal hypoglycemia. We therefore prospectively studied 122 pregnancies in 100 well-controlled insulin-dependent diabetic mothers. Intravenous glucose and/or insulin was infused during labor to maintain capillary glucose concentration between 70 and 100 mg/dl. Fifty-six pregnancies were concluded by primary or elective cesarean section (group 1), 36 by cesarean section following spontaneous or induced labor (group 2), and 30 by spontaneous or induced vaginal delivery (group 3). Hemoglobin A1, birthweight, and gestational age were similar in all three groups. The rate of neonatal polycythemia was significantly lower in the cesarean section subjects, groups 1 and 2, as compared to group 3 (P less than 0.04). The rate of neonatal hyperbilirubinemia was significantly lower in group 1 (P less than 0.05) as compared to groups 2 and 3. The rate of RDS was higher in group 1 (versus groups 2 or 3), but did not reach significance on initial analysis (P = 0.06); however, group 1 was associated with a significant risk for RDS when corrected for the confounding variables of gestational age and neonatal asphyxia as defined by Apgar scores.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2006

Method for chronological recording of antigen appearance in human head-hair shafts and its use for monitoring glycation products in diabetes.

We describe immunochemical assays of non-enzymatic glycation products in human head-hair protein extracts and hair cross sections using Western blots and a novel "dot-block" methodology. In the latter, groups of approximately 15 hair fibers, clipped at about 1 mm proximal to the scalp-skin were aligned, wound around, and attached to 3 mm diameter araldite screw rods. Up to 40 such rods were next embedded lengthwise in additional araldite polymer creating a solid block and the top surface of the block was sectioned off to the half-diameters of the screw rods thus exposing accurately transected hair cross sections at regular ( approximately 0.5 cm) intervals. Early- and advanced-glycation products (EGAs and AGEs, respectively) were determined in the exposed cross sections in-situ using specific antibodies and ECL densitometry as in conventional Western blots. Both Western blots and this technique demonstrated 3.1 fold EGAs increases in the proximal 2 cm of hair of diabetics as compared to non-diabetics. Dot-blocks, in addition, were less variable and demonstrated exponential EGAs decreases along fibers distally, with calculated intercepts (at the hair roots) of 4.9 fold increases in diabetics as opposed to non-diabetics and half-lives of 6.0, 5.9 and 9.0 months in hair of non-diabetics, gestational diabetics and diabetic patients, respectively. Correlations in amounts of BG vs. HbA1(c), BG vs. EGAs, and HbA1(c) vs. EGAs, using dot-block and clinical lab data were all significant (p<0.05). Acute onset T1D patients, defined as previously unsuspected patients diagnosed upon hospitalization due to diabetic complications, exhibited nearly identical EGAs levels in their proximal 0-9 cm hair as did T1D patients with long-established diabetes, thus supporting the notion of long and insidious T1D etiology. Removal of 1-2 microm layers from dot-block surfaces enabled their re-use for multiple assays. Applied anti-AGEs antibodies demonstrated slight decreases or no significant changes in CML and MGI along hair shafts of normal and diabetic subjects. Fluctuations in EGAs and AGEs along hair shafts, indicating alterations in glycemic control were also observed. We conclude that the dot-block method has a potential for early diagnosis and monitoring of diabetes, and more generally, as a long term "biological record" of various chronic medical conditions.

Adult↗

PubMed2000

Enhanced acute-phase response and oxidative stress in older adults with type II diabetes.

OBJECTIVE: To test whether oxidative stress could promote a systemic acute-phase response in elderly patients with type II diabetes. DESIGN AND METHODS: In a group of 30 older diabetic patients with poor glycemic control, serum levels of lipid peroxides, measured as thiobarbituric acid-reacting substances (TBARS); C-reactive protein (CRP); interleukin (IL)-6 and the soluble form of its receptor (slL-6R), were evaluated at baseline and after 2 and 3 months of therapeutic intervention. Thirty asymptomatic, untreated individuals with abnormal fasting glycemia, but otherwise healthy status, of similar age, sex, and weight served as control group. RESULTS: At baseline, glycemia (8.83 +/- 0.67mmol/l), HbA1C (8.66 +/- 0.59%), TBARS (8.68 +/- 1.21 micromol/l), CRP (16.05 +/- 3.81 mg/l) IL-6 (5.39 +/- 1.25 pg/ml) and sIL-6R (1425 +/- 492 pg/ml) were significantly higher in diabetic patients than in asymptomatic hyperglycemic individuals (p<0.001). After treatment, glycemia significantly decreased with respect to baseline values (- 9.82% after 60 days and -13.74% after 90 days), as did serum levels of TBARS (-14.05% and -21.89%, respectively), CRP (-32.71% and -43.86%), IL-6 (-23.75% and -40.63%) and sIL-6R (-34.53% and -48.49%, respectively). In diabetic patients, multiple regression showed, at each time, that TBARS and IL-6 were independently correlated with CRP, considering CRP as the dependent variable. Similar correlations were found in asymptomatic hyperglycemic subjects. CONCLUSION: These results suggest that oxidative stress might be implicated in promoting a state of low-grade systemic inflammation in elderly patients with type II diabetes.

Acute-Phase Reaction↗

PubMed1986

Effect of sera from male type 2 (non-insulin-dependent) diabetics on human aortic smooth muscle cells in culture.

The effect of sera from male type 2 (non-insulin dependent) diabetics in variable metabolic control on the proliferation of, and on the synthesis of hyaluronic acid and collagen in human aortic smooth muscle cells (HSMCs) in culture was studied. Pooled sera from diabetics in poor metabolic control either with or without antidiabetic drugs stimulated the proliferation and hyaluronic acid synthesis of the cells more than did pooled serum from healthy controls. On the other hand, pooled serum from diabetics in good metabolic control did not have a higher stimulatory effect on the growth of HSMCs than pooled control serum. Indeed, it increased the synthesis of hyaluronic acid similarly as did the pooled serum from poorly controlled diabetics. The synthesis of collagen was not affected by pooled diabetic sera. When the effects of 14 male diabetic sera were individually measured using the same functions of HSMCs, metabolic control of diabetes did not correlate with various activities of diabetic sera on HSMCs. The results show that sera of type 2 diabetics contain factors affecting the functions of HSMCs. The activity of the factors on cell proliferation is related to some extent to the degree of glycemic control, as shown in experiments with serum pools, but experiments with individual sera show that other serum properties unrelated to the metabolic control of diabetes are also of importance.

Blood Glucose↗

PubMed2003

Low IGF-I and elevated testosterone during puberty in subjects with type 1 diabetes developing microalbuminuria in comparison to normoalbuminuric control subjects: the Oxford Regional Prospective Study.

OBJECTIVE: To describe longitudinal variations in pubertal hormonal variables in subjects with and without microalbuminuria (MA). RESEARCH DESIGN AND METHODS: Blood samples collected annually from subjects recruited at diagnosis of type 1 diabetes and followed prospectively through puberty (median follow-up 9.3 years, range 4.7-12.8) were analyzed for total and free IGF-I, IGF binding protein-1, testosterone, sex hormone-binding globulin, and HbA(1c). A total of 55 subjects who developed MA (MA(+) group) were compared with 55 age-, sex-, and duration-matched control subjects who did not develop MA (MA(-) group). RESULTS: For female subjects, total IGF-I (MA(+) 1.2 mU/l vs. MA(-) 1.4 mU/l, P = 0.03) and free IGF-I levels (MA(+) 1,767 ng/l vs. MA(-) 2010 ng/l, P = 0.002) were lower, whereas the free androgen index (MA(+) 2.4 vs. MA(-) 2.0, P = 0.03) was higher in those with MA. These changes were less pronounced in male subjects. For both sexes, in a Cox model after adjusting for puberty, the presence of MA was associated with lower free IGF-I levels, higher testosterone standard deviation score (SDS), and poor glycemic control. We found that 22 of 55 case subjects (40%) developed persistent MA, whereas 33 (60%) had transient MA. In the persistent MA group compared with the transient and control groups, total IGF-I levels were lower (1.1 vs. 1.3 vs. 1.4 mU/l, P = 0.002) as were free IGF-I levels (1,370.9 vs. 1,907.3 vs. 1,886.7 ng/l, P < 0.001), whereas HbA(1c) levels were higher (11.8 vs. 10.3 vs. 9.9%, P < 0.001). CONCLUSIONS: Poor glycemic control and differences in IGF-I levels and androgens, particularly in female subjects, accompany development of MA at puberty. These differences may in part account for the sexual dimorphism in MA risk during puberty and could relate to disease progression.

Adolescent↗

PubMed1985

Glycemic control in diabetic dogs treated with pancreatic autotransplants and insulin pumps.

The restoration of metabolic control in diabetes mellitus is predicated upon the uniform achievement of fasting euglycemia. In the absence of fasting normoglycemia, metabolic control is fundamentally compromised. We asked whether the currently experimental methods of treating experimental diabetes are capable of achieving normality in this regard. We therefore examined fasting plasma glycemia prospectively in a group of normal animals. This important index of metabolic homeostasis was remarkably tightly controlled with a mean +/- SD of 94 +/- 5 mg/dl. As a model of diabetes, we pancreatectomized a similar but larger group of animals. Some received grafts of their own pancreas while some received exogenous insulin by continuous intravenous infusion using an external pump. Half of this infused group received the insulin portally while the other half received it peripherally. Although our findings were globally similar to what has been reported previously, we elucidated subtle differences which heretofore have not been considered. Fist of all, the mean +/- SD fasting plasma glucose (FPG) concentration in the group of transplanted animals was 103 +/- 16 mg/dl, significantly higher than normal (p less than 0.001). It was, however, similar to the supra-normal levels we observed in the peripherally infused animals (100 +/- 25 mg/dl). Only the portally infused dogs had FPG levels of 95 +/- 27 mg/dl entirely similar to the normal controls. Most remarkably, all treatment methods resulted in variations in FPG levels which were significantly greater than normal (p less than 0.001), with coefficients of variation 3-5 times normal. Whether in the autotransplanted animals this variability represented the peripheral route of endogenous insulin replacement or the aneural nature of the transplanted gland was not clarified.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2006

Insulin detemir: a long-acting insulin product.

PURPOSE: The pharmacology, pharmacokinetics, efficacy and tolerability, safety, drug interactions, dosage and administration, cost, and place in therapy of insulin detemir are reviewed. SUMMARY: Insulin detemir is a long-acting, neutral, and soluble insulin analogue with a lower within-subject variability of fasting plasma glucose levels than isophane insulin human (NPH insulin) and insulin glargine. The lower within-subject variability of insulin detemir may decrease hypoglycemic events, especially nocturnal events, and may contribute to a decreased incidence of weight gain. In vivo, insulin detemir is 98-99% bound to albumin-one of the mechanisms contributing to its long duration of action. Several open-labeled, randomized, multicenter trials have been conducted comparing the safety and efficacy of insulin detemir to NPH insulin in patients with type 1 or type 2 diabetes mellitus. In most trials, patients were randomized to receive insulin on three different dosing schedules: basal insulin twice daily before breakfast and at bedtime, basal insulin at 12-hour intervals, or basal insulin before breakfast and dinner. Mealtime insulin was given as part of the basal-bolus therapy. Glycosylated hemoglobin values were similar in patients receiving insulin detemir or NPH insulin. Insulin detemir appears to be well tolerated. The most common adverse effects reported during clinical trials were hypoglycemia, headache, dizziness, and injection-site reactions. CONCLUSION: Insulin detemir given once or twice daily as part of basal-bolus insulin therapy is at least as effective as NPH insulin in maintaining overall glycemic control in adult patients with type 1 or type 2 diabetes mellitus.

Adult↗

PubMed1996

Exogenous insulin administration and cardiovascular risk in non-insulin-dependent and insulin-dependent diabetes mellitus.

PURPOSE: It is currently unknown whether intensive insulin treatment of diabetes decreases the risk for cardiovascular complications by lowering glucose levels or increases the risk by postulated direct atherogenic effects. This article reviews published data from two long-term, randomized clinical trials that compared cardiovascular outcomes associated with different exogenous insulin treatment regimens. STUDY SELECTION AND DATA SOURCES: The University Group Diabetes Program (UGDP) and the Diabetes Control and Complications Trial (DCCT) were selected as the only available randomized intervention trials with long-term follow-up results. Data reviewed were from the major publications of these two trials. RESULTS: The UGDP compared the effects of a fixed-dose standard insulin regimen, a variable-dose insulin regimen, and a diet plus oral placebo regimen in over 600 patients with non-insulin-dependent diabetes mellitus (NIDDM) who were followed for up to 13 years (1962 to 1975). Plasma glucose levels were 1.7 to 2.2 mmol/L lower in the variable-dose insulin regimen group than in the other two treatment groups. No significant differences were found in the final prevalence or the cumulative incidence of total deaths, cardiovascular disease deaths, or myocardial infarctions among the three treatment groups, even when outcomes were adjusted for pertinent baseline cardiovascular risk factors. There was a slight suggestion only from post hoc analysis that patients in both insulin treatment groups, who were defined as having good glucose control, had fewer cardiovascular events than those with fair or poor control. The DCCT compared intensive insulin treatment with conventional insulin treatment (the mean hemoglobin A1c [HbA1c] level was 7.2% and 9.0%, respectively) in over 1400 patients with insulin-dependent diabetes (IDDM) followed for up to 10 years (1983 to 1993). Three major cardiovascular events occurred in the intensive treatment group as compared with 14 in the conventional treatment group (P > 0.05), and low-density lipoprotein cholesterol and triglyceride levels were substantially lower in the intensive treatment group. However, body mass index increased substantially more with intensive than with conventional therapy. CONCLUSIONS: The UGDP trial was flawed by inadequate power, insufficient separation of glycemic levels, and ignorance of smoking history as a possible confounder. In the DCCT, the number of cardiovascular events was few because the patients were young and had a relatively short duration of diabetes at baseline. In addition, total daily insulin doses were similar in the two DCCT treatment groups. For these reasons, neither trial provides a definitive answer to the question about the effects of intensive insulin therapy. A better designed clinical trial is needed to determine whether insulin treatment has beneficial or adverse effects, or even offsetting beneficial and adverse effects, on the risk for cardiovascular disease in NIDDM and IDDM.

Blood Glucose↗

PubMed1995

Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus.

BACKGROUND: There is little information on the incidence and natural history of neuropathy in patients with non-insulin-dependent diabetes mellitus (NIDDM). METHODS: We studied patients with newly diagnosed NIDDM and control subjects both at base line and 5 and 10 years later. Polyneuropathy was diagnosed on the basis of clinical criteria (pain and paresthesias) and electrodiagnostic studies (nerve conduction velocity and response-amplitude values). We investigated the relation between metabolic variables (results of oral glucose-tolerance tests, serum lipid and insulin concentrations, and glycosylated hemoglobin values) and the development of polyneuropathy. RESULTS: In 10 years, 36 patients with NIDDM and 8 control subjects died; 86 patients and 121 control subjects completed the study. When the study ended, 18 percent of the patients were being treated only with diet, 59 percent with oral hypoglycemic drugs alone, 12 percent with insulin alone, and 11 percent with both insulin and oral hypoglycemic agents. At base line the prevalence of definite or probable polyneuropathy among the patients with NIDDM was 8.3 percent, as compared with 2.1 percent among the control subjects. These values 10 years later were 41.9 percent and 5.8 percent, respectively. The number of patients with NIDDM who had nerve-conduction abnormalities in the legs and feet increased from 8.3 percent at base line to 16.7 percent after 5 years and to 41.9 percent after 10 years. The decrease in sensory and motor amplitudes, indicating axonal destruction, was more pronounced than the slowing of the nerve conduction velocities, which indicates demyelination. Among the patients with NIDDM, those with polyneuropathy had poorer glycemic control than those without. Low serum insulin concentrations before and after the oral administration of glucose were associated with the development of polyneuropathy, regardless of the degree of glycemia. CONCLUSIONS: The prevalence of polyneuropathy among patients with NIDDM increases with time, and the increase may be greater in patients with hypoinsulinemia.

Blood Glucose↗

PubMed2006

Effects of 1 year of treatment with pioglitazone or rosiglitazone added to glimepiride on lipoprotein (a) and homocysteine concentrations in patients with type 2 diabetes mellitus and metabolic syndrome: a multicenter, randomized, double-blind, controlled clinical trial.

BACKGROUND: Although the metabolic effects of the thiazolidinediones have been well studied, there is a lack of comparative data on their effects on certain cardiovascular risk factors, such as elevated plasma levels of lipoprotein (a) (Lp[a]) and homocysteine (Hcy). OBJECTIVE: This study compared the effects of pioglitazone or rosiglitazone added to glimepiride on a range of lipid parameters, focusing on Lp(a) and Hcy, in patients with type 2 diabetes mellitus and the metabolic syndrome. METHODS: This was a multicenter, randomized, controlled, double-blind study in patients with type 2 diabetes and the metabolic syndrome (hypertension [>or=130/85 mm Hg]) and triglyceridemia (>or=150 mg/dL). In addition to glimepiride 4 mg/d, patients received pioglitazone 15 mg QD or rosiglitazone 4 mg QD for 1 year. The primary efficacy variables were change from baseline in body mass index (BMI), glycosylated hemoglobin (HbA(1c)), Lp(a), and Hey. Secondary efficacy measures were changes in fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) concentrations, fasting and postprandial insulin concentrations (FPI and PPI, respectively), the Homeostasis Model Assessment index, and the lipid profile (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides). All these parameters were measured after a 12-hour fast every 3 months for 1 year. Tolerability was assessed based on reported adverse events and laboratory abnormalities at each study visit. RESULTS: Ninety-one white patients with type 2 diabetes and the metabolic syndrome were enrolled, and 87 completed the study (43 men, 44 women; mean [SD] age, 53 [6] years; mean weight, 68.4 [3.3] kg). Mean baseline values for BMI and HbA(1c) were 24.3 (0.8) kg/m(2) and 8.1 % (0.8 %), respectively. At the end of 1 year, both treatment groups had significant increases from baseline in BMI (4.9% glimepiride + pio glitazone, 6.2% glimepiride + rosiglitazone; P < 0.05). Glimepiride + pioglitazone was associated with the following percent improvements from baseline in measures of glycemic control: -17.1% in HbA(1c), -19.3% in FPG, -17.8% in PPG, -40.1% in FPI, and -22.6% in PPI (all, P < 0.01). The corresponding percent improvements from baseline with glimepiride + rosiglitazone were -16.3%, -19.9%, -15.0%, -44.8%, and -22.1% (all, P < 0.01). There were no significant differences between treatment groups in any of these parameters. The pioglitazone group had significant improvements from baseline in TC (-11.1%), LDL-C (-12.0%), HDL-C (15.0%), and triglycerides (-22.4%) [corrected] (all, P < 0.05), whereas the rosiglitazone group had significant increases in TC (14.9%), LDL-C (16.5%), and triglycerides (17.9%) (all, P < 0.05); the difference between pioglitazone and rosiglitazone was statistically significant (P < 0.05). The change from baseline in Lp(a) was significant in the pioglitazone group, both relative to baseline and compared with the rosiglitazone group (-19.7% vs 0.5%, respectively; P < 0.05 vs baseline and vs rosiglitazone). Changes from baseline in Hey were significant in both the pioglitazone and rosiglitazone groups (-20.2% and -25.0%, respectively; P < 0.05), with no significant difference between groups. Both treatments were well tolerated, and no patients had significant changes in transaminases. CONCLUSIONS: In these patients with type 2 diabetes and the metabolic syndrome, the combinations of glimepiride with pioglitazone and glimepiride with rosiglitazone produced significant improvements in measures of glycemic control, plasma lipids, and homocysteinemia. One year of treatment with the pioglitazone combination was associated with significantly reduced plasma Lp(a) levels compared with the rosiglitazone combination.

Blood Glucose↗

PubMed1999

Safety and efficacy of metformin in a restricted formulary.

OBJECTIVE: To assess the efficacy and safety of metformin (MET) in the Veterans' Administration Northern California Health Care System during the period from June 1995 through April 1996 when its use required approval by Endocrinology. STUDY DESIGN: A retrospective review of patient charts and computerized pharmacy and laboratory records. Patients served as their own historical controls. PATIENTS AND METHODS: Patients receiving MET (n = 251) were identified from the pharmacy database. On-line laboratory data, including the intermediate outcome variable HbA1c, were retrieved by computer for the interval 4 months prior to the initial prescription to May 1996. Clinical data including weight and blood pressure were obtained from chart review. RESULTS: Of 228 patients whose charts were available for review, 29 reported side effects, and 12 discontinued use due to these side effects. No patients were identified with lactic acidosis. Both baseline and treatment data on HbA1c were available on 164 patients. Mean HbA1c (%) data (unpaired), expressed as mean +/- SE, were as follows: between 4 months pretreatment and 1 month pretreatment, 9.41 +/- 0.19 (n = 103 tests); between 1 month pretreatment and baseline, 9.41 +/- 0.19 (n = 110 tests); 3 months of treatment, 8.79 +/- 0.16 (n = 157 tests, P < 0.05); 6 months of treatment, 8.30 +/- 0.17 (n = 79 tests, P < 0.0001); 9 months of treatment, 8.72 +/- 0.24 (n = 70 tests, P < 0.05), compared to pretreatment values. Similar analysis of unpaired weight and blood pressure data in 152 patients did not reveal any reduction in these clinical parameters over this treatment period. Serum lipids were unchanged on treatment (by paired analysis), but the number of tests was limited. CONCLUSION: In this setting, MET provided sustained beneficial effects on glycemic control and was well tolerated. Any effects on weight, blood pressure, and serum lipids were not demonstrable in this analysis. We conclude that MET can substantially improve outcome of diabetes care.

Blood Pressure↗

PubMed1988

Studies of cardiovascular and renal function in subclinical and manifest diabetic nephropathy.

Cardiovascular and Renal function were examined in two populations of long-term insulin-dependent diabetics, those with microalbuminuria, a sign of early, subclinical nephropathy and those with clinically manifest diabetic nephropathy. In addition, clinical variables of possible importance for the occurrence and prognosis of diabetic nephropathy were analyzed. Microalbuminuria - a mean of three over-night urinary albumin excretion rates greater than 20 micrograms/min - was found in 16% of Albustix-negative, normotensive, insulin-dependent diabetics. The microalbuminurics had higher supine blood pressures than normoalbuminurics. The albumin excretion rate in microalbuminurics correlated to blood pressure at rest but not to glycosylated haemoglobin. The cardiovascular responses to five different test manoeuvres revealed more evident signs of autonomic nerve dysfunction in microalbuminurics than in normoalbuminurics. The circulatory reactions during mental stress however, were almost identical in the two subgroups. Despite similar glomerular filtration rate and renal plasma flow the albumin excretion during mental stress increased in microalbuminurics, but remained unchanged in normoalbuminurics. It is postulated that a disturbance of glomerular basement membrane permeability is a pre-requisite for the elevated albumin excretion seen in microalbuminurics. Inability to regulate glomerular haemodynamics, due to autonomic nerve dysfunction, may also be a contributing factor. Such dysfunction perhaps even explains why microalbuminurics have higher blood pressures at rest compared with normoalbuminurics. In manifest diabetic nephropathy the rate of renal functional decline correlated to arterial blood pressure, while glycemic control showed no such relation. Patients with rapidly progressive nephropathy showed higher values of growth hormone than slow progressors. In patients with diabetic renal failure, cardiac catheterization revealed reduced stroke work and elevated left ventricular end-distolic pressure during exercise. Autonomic nerve dysfunction and arterial hypertension possibly contributed to the impaired cardiac performance. The existence of a specific diabetic cardiopathy must even be considered. There was a male predominance both in subclinical and manifest diabetic nephropathy. Age at onset of diabetes was lower in micro- as compared to normoalbuminurics. Duration of diabetes had no prognostic implication in subclinical or manifest nephropathy. The mortality rate was high in patients with manifest nephropathy.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1989

Clinical evaluation of serum fructosamine in monitoring elderly outpatient diabetics.

Recently, new serum glycated protein assays (ie, serum fructosamine) have been developed. Fructosamine assays objectively monitor short-term glycemic control and, when used in conjunction with HgA1C, enhance the clinical information obtained and greatly aid in the clinical management of diabetes. Because they rely on glycation of serum proteins, the clinical utility of these assays in the elderly may be altered secondary to the hypoproteinemia that often is seen in these states. Therefore, we investigated the role of glycated serum proteins (ie, fructosamine level) in monitoring elderly diabetics over a 4-month period of observation. We found that the fasting blood glucose over the 4-month period correlated well with the serum fructosamine activity (r = 0.79, P less than .001) and HgA1C (r = 0.78, P less than .001). In addition, we found that the mean daily glucose, as determined by outpatient monitoring, correlated well to both the fructosamine activity (r = 0.66, P less than .001) and HgA1C (r = 0.74, P less than .001). We found no effect on the measurement of the fructosamine assay by the level of albumin seen in these patients. Our study suggests that serum fructosamine and HgA1C are equally effective in monitoring the elderly patient, as has been established in the younger diabetic, and no correction need be made in the fructosamine assay to compensate for variable serum protein levels seen clinically in the elderly.

Aged↗