bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Exenatide (Exendin-4) on Glycemic Control Over 30 Weeks in Patients With Type 2 Diabetes Treated With Metformin and a Sulfonylurea
Authors: Kendall David M. , Riddle Matthew C. , Rosenstock Julio , Zhuang Dongliang , Kim Dennis D. , Fineman Mark S. , Baron Alain D.
Published: March 2007

OBJECTIVE—This study evaluated the effects of exenatide, a novel incretin mimetic, in hyperglycemic patients with type 2 diabetes unable to achieve glycemic control with metformin-sulfonylurea combination therapy.

RESEARCH DESIGN AND METHODS—A 30-week, double-blind, placebo-controlled study was performed in 733 subjects (aged 55 ± 10 years, BMI 33.6 ± 5.7 kg/m2, A1C 8.5 ± 1.0%; means ± SD) randomized to 5 μg subcutaneous exenatide b.i.d. (arms A and B) or placebo for 4 weeks. Thereafter, arm A remained at 5 μg b.i.d. and arm B escalated to 10 μg b.i.d. Subjects continued taking their dose of metformin and were randomized to either maximally effective (MAX) or minimum recommended (MIN) doses of sulfonylurea.

RESULTS—Week 30 A1C changes from baseline (±SE) were −0.8 ± 0.1% (10 μg), −0.6 ± 0.1% (5 μg), and +0.2 ± 0.1% (placebo; adjusted P < 0.0001 vs. placebo), yielding placebo-adjusted reductions of −1.0% (10 μg) and −0.8% (5 μg). In the evaluable population, exenatide-treated subjects were more likely to achieve A1C ≤7% than placebo-treated subjects (34% [10 μg], 27% [5 μg], and 9% [placebo]; P < 0.0001). Both exenatide arms demonstrated significant weight loss (−1.6 ± 0.2 kg from baseline each exenatide arm, −0.9 ± 0.2 kg placebo; P ≤ 0.01 vs. placebo). Mild or moderate nausea was the most frequent adverse event. The incidence of mild/moderate hypoglycemia was 28% (10 μg), 19% (5 μg), and 13% (placebo) and appeared lower with MIN than with MAX sulfonylurea treatment.

CONCLUSIONS—Exenatide significantly reduced A1C in patients with type 2 diabetes unable to achieve adequate glycemic control with maximally effective doses of combined metformin-sulfonylurea therapy. This improvement in glycemic control was associated with no weight gain and was generally well tolerated.
Effects of Exenatide (Exendin-4) on Glycemic Control and Weight Over 30 Weeks in Metformin-Treated Patients With Type 2 Diabetes
Authors: DeFronzo Ralph A. , Ratner Robert E. , Han Jenny , Kim Dennis D. , Fineman Mark S. , Baron Alain D.
Published: March 2007

OBJECTIVE—This study evaluates the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing to achieve glycemic control with maximally effective metformin doses.

RESEARCH DESIGN AND METHODS—A triple-blind, placebo-controlled, 30-week study at 82 U.S. sites was performed with 336 randomized patients. In all, 272 patients completed the study. The intent-to-treat population baseline was 53 ± 10 years with BMI of 34.2 ± 5.9 kg/m2 and HbA1c of 8.2 ± 1.1%. After 4 weeks of placebo, subjects self-administered 5 μg exenatide or placebo subcutaneously twice daily for 4 weeks followed by 5 or 10 μg exenatide, or placebo subcutaneously twice daily for 26 weeks. All subjects continued metformin therapy.

RESULTS—At week 30, HbA1c changes from baseline ± SE for each group were −0.78 ± 0.10% (10 μg), −0.40 ± 0.11% (5 μg), and +0.08 ± 0.10% (placebo; intent to treat; adjusted P < 0.002). Of evaluable subjects, 46% (10 μg), 32% (5 μg), and 13% (placebo) achieved HbA1c ≤7% (P < 0.01 vs. placebo). Exenatide-treated subjects displayed progressive dose-dependent weight loss (−2.8 ± 0.5 kg [10 μg], −1.6 ± 0.4 kg [5 μg]; P < 0.001 vs. placebo). The most frequent adverse events were gastrointestinal in nature and generally mild to moderate. Incidence of mild to moderate hypoglycemia was low and similar across treatment arms, with no severe hypoglycemia.

CONCLUSIONS—Exenatide was generally well tolerated and reduced HbA1c with no weight gain and no increased incidence of hypoglycemia in patients with type 2 diabetes failing to achieve glycemic control with metformin.
Decreased Lung Function in Female but not Male Subjects With Established Cystic Fibrosis–Related Diabetes
Authors: Sims Erika J. , Green Michael W. , Mehta Anil
Published: March 2007

OBJECTIVE—Although cystic fibrosis–related diabetes (CFRD) is associated with decreased lung function, sex is not known to influence CFRD. However, compared with male subjects with cystic fibrosis, female subjects with cystic fibrosis have increased morbidity. This study examines the association between female subjects with CFRD and poor lung function relative to male subjects using the percent predicted forced expiratory volume in 1 s (FEV1) as a surrogate measure of morbidity.

RESEARCH DESIGN AND METHODS—We compared 323 patients with established CFRD with 489 cystic fibrosis control subjects with normal glucose tolerance (NGT) listed in the U.K. Cystic Fibrosis Database. Patients stratified by sex and chronic Pseudomonas aeruginosa infection were compared using binary logistic regression, and patients with new CFRD diagnoses were compared prospectively for the year 2002.

RESULTS—CFRD in female subjects (but not male subjects) without chronic P. aeruginosa infection had a 20% lower percent predicted FEV1 compared with control subjects with NGT (95% CI −11.7 to −27.7; P < 0.0001). Genotype, age, treatment center, age at diagnosis of cystic fibrosis, pregnancy, liver function, or dose of pancreatic enzyme replacement therapy did not confound this female disadvantage. Comparison of female subjects with newly diagnosed CFRD free of chronic P. aeruginosa infection with matched control subjects with NGT showed no FEV1 disadvantage in the 1st year after CFRD diagnosis.

CONCLUSIONS—Only female subjects with CFRD have significantly decreased lung function compared with sex-matched NGT control subjects. The absence of poor lung function in the first 12 months after diagnosis of diabetes suggests that an opportunity may exist to intervene and possibly prevent a decline in lung function, which can be as much as 20% in female subjects with CFRD.
Obesity, Inactivity, and the Prevalence of Diabetes and Diabetes-Related Cardiovascular Comorbidities in the U.S., 2000–2002
Authors: Sullivan Patrick W. , Morrato Elaine H. , Ghushchyan Vahram , Wyatt Holly R. , Hill James O.
Published: March 2007

OBJECTIVE—Obesity and physical inactivity are established risk factors for type 2 diabetes and cardiovascular comorbidities. Whether adiposity or fitness level is more important to health is controversial. The objective of this research is to determine the relative associations of physical activity and BMI with the prevalence of diabetes and diabetes-related cardiovascular comorbidities in the U.S.

RESEARCH DESIGN AND METHODS—The Medical Expenditure Panel Survey (MEPS) is a nationally representative survey of the U.S. population. From 2000 to 2002, detailed information on sociodemographic characteristics and health conditions were collected for 68,500 adults. Normal weight was defined as BMI 18.5 to <25 kg/m2, overweight 25 to ≤30 kg/m2, obese (class I and II) 30 to <40 kg/m2, and obese (class III) ≥40 kg/m2. Physical activity was defined as moderate/vigorous activity ≥30 min ≥3 days per week.

RESULTS—The likelihood of having diabetes and diabetes-related cardiovascular comorbidities increased with BMI regardless of physical activity and increased with physical inactivity regardless of BMI. Compared with normal-weight active adults, the multivariate-adjusted odds ratio (OR) for diabetes was 1.52 (95% CI 1.25–1.86) for normal-weight inactive adults and 1.65 (1.40–1.96) for overweight inactive adults; the OR for diabetes and comorbid hypertension was 1.71 (1.32–2.19) for normal-weight inactive adults and 1.84 (1.47–2.32) for overweight inactive adults.

CONCLUSIONS—Both physical inactivity and obesity seem to be strongly and independently associated with diabetes and diabetes-related comorbidities. These results support continued research investigating the independent causal nature of these factors.
Effect of Hepatic Lipase −514C→T Polymorphism and Its Interactions With Apolipoprotein C3 −482C→T and Apolipoprotein E Exon 4 Polymorphisms on the Risk of Nephropathy in Chinese Type 2 Diabetic Patients
Authors: Baum Larry , Ng Maggie C.Y. , So Wing-Yee , Lam Vincent K.L. , Wang Ying , Poon Emily , Tomlinson Brian , Cheng Suzanne , Lindpaintner Klaus , Chan Juliana C.N.
Published: March 2007

OBJECTIVE—Triglyceride-rich lipoprotein particles may promote the progression of diabetic nephropathy. Patients with diabetic nephropathy have increased plasma triglycerides and reduced activity of hepatic lipase (HL), which hydrolyzes triglycerides. We hypothesized that the HL −514C→T polymorphism, which reduces HL expression, and its interactions with polymorphisms in apolipoprotein (apo) E and apoC3 increase the risk of diabetic nephropathy.

RESEARCH DESIGN AND METHODS—In a case-control study involving 374 Chinese type 2 diabetic patients with and 392 without diabetic nephropathy, we genotyped the HL −514C→T, apoE exon 4, and apoC3 −482C→T polymorphisms.

RESULTS—HL −514T−containing genotypes (T+) were associated with diabetic nephropathy (OR = 1.7, P = 0.0009). Adjustment by multiple logistic regression for hypertension, triglycerides, sex, non-HDL cholesterol, BMI, smoking, and alcohol intake did not diminish the association (OR = 1.8, P = 0.003). The association between HL T+ genotypes and diabetic nephropathy appeared stronger in diabetic patients with apoC3 −482 non-TT genotypes (OR = 1.9, P = 0.003) or apoE ε2 or ε4 alleles (OR = 2.2, P = 0.005). Subjects with HL TT exhibited trends toward increased triglyceride and non-HDL cholesterol levels compared with CC carriers.

CONCLUSIONS—HL T+ genotypes might increase the risk of developing diabetic nephropathy by slowing clearance of triglyceride-rich remnant lipoproteins. In concert with other risk factors (e.g., hyperglycemia), lipid abnormalities may damage the kidneys and endothelium, where reduced binding sites for lipases may precipitate a vicious cycle of dyslipidemia, proteinuria, and nephropathy.
Autoantibodies to Autonomic Nerves Associated With Cardiac and Peripheral Autonomic Neuropathy
Authors: Granberg Viktoria , Ejskjaer Niels , Peakman Mark , Sundkvist Göran
Published: March 2007

OBJECTIVE—This study examines whether autonomic nerve autoantibodies (ANabs) are associated with development of autonomic neuropathy using a prospective study design.

RESEARCH DESIGN AND METHODS—A group of type 1 diabetic patients were followed prospectively with regard to autonomic nerve function on four occasions. At the third examination, 41 patients were tested for ANabs (complement-fixing autoantibodies to the sympathetic ganglion, vagus nerve, and adrenal medulla), and the results were related to cardiac autonomic nerve function (heart rate variation during deep breathing [expiration/inspiration ratio] and heart-rate reaction to tilt [acceleration and brake index]) and to peripheral sympathetic nerve function (vasoconstriction after indirect cooling [vasoconstriction index]).

RESULTS—ANabs were detected in 23 of 41 (56%) patients at the third examination. Compared with patients without ANabs (ANabs−), patients with ANabs (ANabs+) showed significantly higher frequencies of at least one abnormal cardiac autonomic nerve function test at the third examination (17 of 23 [74%] vs. 7 of 18 [39%]; P = 0.03) and fourth examination (15 of 21 [71%] vs. 4 of 16 [25%]; P < 0.01). In contrast, there was no similar difference at the first or second examination. The relative risk for ANabs+ patients to develop cardiac autonomic neuropathy at follow-up was 7.5 (95% CI 1.72–32.80). The vasoconstriction index was more abnormal in ANabs+ than in ANabs− patients at the fourth examination (median 1.40 [interquartile range 1.58] vs. 0.35 [2.05]; P = 0.01).

CONCLUSIONS—ANabs were associated with future development of cardiac and peripheral autonomic neuropathy in diabetic patients, implying an etiological relationship between nervous tissue autoimmunity and these diabetes complications.
An Evaluation of the Efficacy of Methods Used in Screening for Lower-Limb Arterial Disease in Diabetes
Authors: Williams Dean T. , Harding Keith G. , Price Patricia
Published: March 2007

OBJECTIVE—Foot-related disease is the most common cause for hospital admission among the diabetic population. Lower-limb peripheral arterial occlusive disease (PAOD) is a major risk factor in diabetic foot disease. Screening for PAOD commonly includes foot pulses and the ankle-brachial pressure index (ABPI) and/or the toe-brachial pressure index (TBI), but concerns persist regarding their accuracy. We evaluated the efficacy of several commonly used screening methods in different subject populations.

RESEARCH DESIGN AND METHODS—We studied 130 limbs in 68 individuals with no critical ischemia over 8 months. Limbs were grouped on the basis of the presence or absence of diabetes, clinically detectable peripheral neuropathy, and PAOD identified on color duplex imaging. Comparative analyses of foot pulses, the ABPI, the TBI, and distal Doppler waveform analysis were performed.

RESULTS—Foot pulses, the TBI, and qualitative waveform analyses were highly sensitive screening methods in individuals with and without diabetes. However, detectable peripheral neuropathy was associated with a reduced sensitivity and poor specificity of foot pulses, a reduction in sensitivity of the ABPI (71 to 38%), and a reduction in specificity of the TBI (81 to 61%) and qualitative waveform analysis (96 to 66%). Quantitative analysis failed to detect disease with severely damped and low-intensity signals.

CONCLUSIONS—Screening tools that are effective in screening for lower-limb PAOD in the nondiabetic population are less efficacious in diabetes, particularly in the presence of detectable peripheral neuropathy. Qualitative waveform analysis and the TBI were demonstrated to be more effective screening methods than the ABPI and foot pulses particularly in high-risk limbs with detectable peripheral neuropathy.
The Impact of ACE Inhibitors or Angiotensin II Type 1 Receptor Blockers on the Development of New-Onset Type 2 Diabetes
Authors: Gillespie Effie L. , White C. Michael , Kardas Michael , Lindberg Michael , Coleman Craig I.
Published: March 2007

OBJECTIVE—Angiotensin II has been shown to increase hepatic glucose production and decrease insulin sensitivity. Patients who utilize either an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) may experience a decreased incidence of new-onset type 2 diabetes.

RESEARCH DESIGN AND METHODS—Three reviewers conducted a systematic literature search of Medline, EMBASE, CINAHL, and the Cochrane Library (1966 to present) to extract a consensus of trial data involving an ACEI or ARB with an end point of new-onset type 2 diabetes. Studies were included if they were randomized controlled trials verses placebo/routine therapy. A random-effects model was utilized. Subgroup and sensitivity analyses were conducted.

RESULTS—Eleven trials were identified, including 66,608 patients. An ACEI or ARB prevented new-onset type 2 diabetes (odds ratio 0.78 [95% CI 0.73–0.83]). The influence of either an ACEI (six trials) or an ARB (five trials) alone on new-onset type 2 diabetes was similar (0.79 [0.71–0.89] and 0.76 [0.70–0.82], respectively). Regardless of indication for use, hypertension (seven trials), coronary artery disease (two trials), or heart failure (two trials), reductions in new-onset type 2 diabetes were maintained (0.79 [0.72–0.85], 0.76 [0.60–0.95], and 0.70 [0.50–0.96], respectively). No statistical heterogeneity was observed for any evaluation (P > 0.1 for all comparisons). ACEIs and ARBs did not reduce the odds of mortality, cardiovascular, or cerebrovascular events versus control therapy among all of these studies combined or the hypertension trials. ACEIs and ARBs did reduce the odds of these outcomes among the coronary artery disease studies versus control therapy.

CONCLUSIONS—ACEIs or ARBs may decrease patients’ odds of developing new-onset type 2 diabetes but does not reduce the odds of mortality, cardiovascular, or cerebrovascular outcomes over the study follow-up periods among patients with hypertension.
Clinic- Rather than Self-Monitoring of Home Blood Samples: Relevance of Day-to-Day Variability to Decision Making
Authors: Ward E A , Phillips M A , Ward G M , Simpson R W , Mullins R , Turner R C
Published: March 2007

The day-to-day variability of blood glucose concentrations in juvenile diabetes means that it is often more reasonable to aim to achieve a generally good pattern of blood glucose control, rather than regularly to assess the next insulin dose after each blood glucose measurement. This means that immediate assessment by the patient of his blood glucose concentrations is not always necessary. We have investigated control in 22 insulin-requiring diabetic patients by means of a monthly series of four blood samples taken during a day into collector bottles and transported to a laboratory for blood glucose assay. The overall means before breakfast, before lunch, before dinner, and before bed were 6.1, 5.8, 7.3, and 7.2 mmol/L, respectively. In many patients, sufficiently good control can be obtained by this method so that it is not necessary to ask them to measure their own blood glucose concentrations or to ask them to obtain the fairly expensive meters for reading glucose oxidase strips. Control would then probably be best assessed by a series of three daily profiles taken once per month, with, if necessary, the results being discussed with the patient. On the other hand, in more unstable diabetes, home assessment by patients of blood glucose measurements is indicated.
Insulin Treatment and High Risk Groups
Authors: O'Sullivan John B , Mahan Clare M
Published: March 2007

A 16-yr prospective study of 615 gestational diabetic subjects, half of whom were randomly assigned to insulin therapy during pregnancy, is evaluated to report on the potential reduction in subsequent diabetes due to insulin therapy. No such difference in incidence rates was observed between the two groups. In the subsets of women managed with insulin who bore a baby of large birthweight or who had a family history of diabetes, subsequent decompensated diabetes was found to be significantly reduced. Both life table and multivariate analyses to adjust for the effects of age, weight, level of blood glucose at selection, duration of follow-up, and other potentially confounding covariables confirmed this conclusion. The finding suggests the possibility of long-term preventive benefits from insulin treatment in high risk subsets of women with gestational diabetes.
Glycosylated Hemoglobin in Diabetes Mellitus: Correlations with Fasting Plasma Glucose, Serum Lipids and Glycosuria
Authors: Aleyassine H , Gardiner R J , Tonks D B , Koch P
Published: March 2007

The levels of glycosylated hemoglobin (GlHb), fasting plasma glucose (FPG), urine glucose, serum triglycerides, cholesterol, and HDL-cholesterol were monitored in several hundred patients attending an adult diabetic clinic. Thirty-five percent of the patients were being treated with insulin, 30% with diet alone, and 20% with sulfonylurea. Therapy was changed during the study in the remaining 15%. The levels of GlHb and FPG were significantly lower in the patients treated with diet alone than in the other groups. The overall coefficient of correlation (r) between FPG and GlHb was 0.64, with the highest r (0.70) for the diet group and the lowest r (0.55) for the insulin group. A follow-up study showed that in about 50% of the patients GlHb and FPG levels changed in different directions from one visit to the next. The absence of glycosuria was noted in two-thirds of the patients, while in 78% of the patients GlHb values were above the normal range. A weak but positive correlation was found between GlHb and serum triglycerides and cholesterol. There was no significant correlation between GlHb and HDL-cholesterol. The HDL-cholesterol levels were significantly lower in male than in female diabetic subjects, but no significant difference was found between the diabetic and nondiabetic subjects of the same sex. The results of this study suggest that (1) although there is a positive correlation between GlHb and FPG, the two tests cannot be used interchangeably in the evaluation of diabetic control; and (2) in the majority of the patients the absence of glycosuria tends to create the false assurance of satisfactory blood glucose control.
Changes in Basement Membrane Thickening and Pulse Volume Concomitant with Improved Glucose Control and Exercise in Patients with Insulin-dependent Diabetes Mellitus
Authors: Peterson Charles M , Jones Robert L , Esterly James A , Wantz George E , Jackson Robert L
Published: March 2007

Ten patients with type I diabetes mellitus were enrolled in a program of exercise and carbohydrate “control” using self-monitored glucose determinations and self-adjusted insulin. Glucose control was improved for the group, although normoglycemia was not uniformly achieved. Pulse volume measurements performed at the onset and after 8–10 mo documented a drop in systolic arm blood pressure with increases in the ankle-arm index (P < 0.001). Quadriceps biopsy was successfully performed at the beginning and after 8–10 mo for analysis of basement membrane thickening (BMT) in seven patients. Six patients showed a decrease in basement thickening on rebiopsy (P = 0.02). One patient showed increased BMT. This was the only patient to maintain a mean hemoglobin A1c of greater than 10% for the duration of the study. These observations indicate that abnormalities of BMT and pulse volume recordings may be more labile measurements than previously thought and may be amenable to therapeutic intervention. The relationship of these variables to the severe micro- and macrovascular sequelae of diabetes mellitus remains to be established.
Plasma Antithrombin III and Thrombin Generation Time: Correlation with Hemoglobin A1 and Fasting Serum Glucose in Young Diabetic Women
Authors: Sowers James R , Tuck Michael L , Sowers Pilek K
Published: March 2007

Three parameters of coagulability – thrombin generation time (TGT), antithrombin III (AT III), and activated partial thromboplastin time (ATPP) – and two parameters of diabetic control – serial measurements of fasting serum glucose (FG) and hemoglobin A1(HbA1) – were used to study the relationship between diabetic control and hypercoagulability. Four groups of females were studied consisting of 10 young normal, 10 young insulin-dependent diabetic, 10 pregnant nondiabetic, and 8 first-trimester, insulin-dependent, pregnant diabetic subjects. Fasting serum glucose values and HbA1 were higher (P < 0.005) in nonpregnant diabetic subjects (193.1 ± 29.1 mg/dl, 12.9 ± 1.1%) and pregnant diabetic subjects (111.0 ± 13.6 mg/dl, 8.2 ± 1.7%) than in controls (64.8 ± 4.4 mg/dl, 5.9 ± 0.1%) and the nondiabetic pregnant females (71.6 ± 3.8 mg/dl, 6.1 ± 0.2%). Young diabetic females, pregnant females, and pregnant diabetic subjects had a shorter (P < 0.01) TGT than did the controls. AT III was greater (P < 0.01) for controls (99.7 ± 2.7%) than for pregnant nondiabetic (83.2 ± 3.8%), diabetic (79.5 ± 2.5%), and pregnant diabetic subjects (76.2 ± 4–4%). There was a positive correlation (r = 0.88, P < 0.005) between HbA1 and FG in the 10 young diabetic and in the 8 pregnant diabetic subjects (r = 0.74, P < < 0.05). In the 10 diabetic females there was a negative correlation between AT III andFG(r = -0.76, P < 0.01) and between AT III and HbA1 (r = -0.79, P < 0.01). Thus, AT III is depressed in both diabetes and pregnancy, with pregnant diabetic subjects displaying the lowest AT III levels. Our observation that depression of AT III levels in young diabetic females was closely correlated with elevations of fasting serum glucose and HbA1 suggests that strict diabetic control may help prevent hypercoagulability in diabetes.
Hypoglycemia and Hemostatic Parameters in Juvenile-onset Diabetes
Authors: Hilsted J , Madsbad S , Nielsen J Dalsgaard , Krarup T , Sestoft L , Gormsen J
Published: March 2007

Hypoglycemia was induced by intravenous infusion of insulin in six juvenile-onset diabetic subjects. Hemostatic parameters were assessed before insulin infusion and 0, 1, and 2 h after discontinuation of insulin infusion. The onset of hypoglycemia coincided with an enhancement of ADP-induced platelet aggregation in five of the patients; platelet aggregation returned to normal levels during the next 2 h. The recalcification time was significantly shortened at the onset of hypoglycemia and continued to decrease for the next 2 h despite the return of serum glucose to normal levels. Correspondingly, a significant increase in fibrinogen was found. The ethanol gelation test was positive in two patients 2 h after stopping insulin infusion. Platelet counts decreased significantly after stopping insulin infusion. Thus, insulin-induced hypoglycemia markedly affects hemostatic balance and may potentially lead to intra-vascular coagulation in juvenile-onset diabetic patients.
The Plasma Glucose Response of Normal Fasting Subjects to Neutral Regular and NPH Biosynthetic Human and Purified Pork Insulins
Authors: Galloway John A , Spradlin C T , Root M A , Fineberg S E
Published: March 2007

Using doses of 0.1 and 0.15 U/kg, the hypoglycemic activities of neutral regular and NPH biosynthetic human insulin (BHI) and purified pork insulin were compared in normal fasting subjects. Neutral regular insulin was administered by the intravenous and subcutaneous routes and NPH subcutaneously. Comparison of the plasma glucose curves disclosed no statistically significant differences between the maximum effects and the length of time to achieve the maximum effect. Moreover, a dose-response difference between 0.1 and 0.15 U/kg could not established. It is concluded that the hypoglycemic activities of neutral regular and NPH BHI and purified pork insulin are the same.
Sucrose and Disease
Authors: Nuttall Frank Q , Gannon Mary C
Published: March 2007

Data currently available indicate that high sucrose consumption does not contribute significantly to the prevalence of cardiovascular disease, diabetes mellitus, obesity, or micronutrient deficiency. It may contribute, however, to dental caries formation by cariogenic bacteria.
Fenfluramine Therapy in Non-insulin-dependent Diabetic Patients: Effects on Body Weight, Glucose Homeostasis, Serum Lipoproteins, and Antipyrine Metabolism
Authors: Salmela P I , Sotaniemi E A , Viikari J , Solakivi-Jaakkola T , Järvensivu P
Published: March 2007

The usefulness of fenfluramine (F), in association with diet therapy, was investigated in 13 obese noninsulin- dependent diabetic patients with poor diabetes control on a previous sulfonylurea regimen (SU). A double-blind crossover comparison of F and placebo (P) consisted of two 7-wk treatment periods. F was administered in stepwise increased and subsequently reduced doses, while the doses of SU were kept unchanged. There was a significant weight loss in F-treated obese subjects as compared with treatment by P. The fasting levels, and particularly the postprandial blood glucose (BG) levels, were significantly lower during F than during P administration. Serum fasting insulin and blood lactate concentrations remained unchanged during the trial. Serum triglycerides and cholesterol decreased during F administration. HDL-cholesterol and apoprotein A-I increased slightly, while apoprotein B decreased during F, but not during P administration. The effect of fenfluramine on hepatic drug metabolism was assessed by using the antipyrine test. F did not cause significant changes in antipyrine metabolism. Fenfluramine therefore seems to be useful as an adjunct to diet and SU therapy in obese non-insulin-dependent diabetic patients.
A Prospective Study of Symptomatic Hypoglycemia in Young Diabetic Patients
Authors: Goldstein David E , England Jack D , Hess Randall , Rawlings Sharon S , Walker Beth
Published: March 2007

The frequency of symptomatic hypoglycemia was determined prospectively over an 18-mo period in 147 children and adolescents with diabetes mellitus. All patients were treated with two daily injections of insulin. The data were analyzed to determine the relationship between episodes of symptomatic hypoglycemia and blood glucose control as assessed by hemoglobin A1c measurements. There were 542 patient visits during the study period. During each clinic visit, patients were separated into one of four hypoglycemic categories based on the medical history since the preceding visit. These categories were: no reactions, mild to occasional reactions, mild to frequent reactions, and severe reactions. Reactions were considered severe if they were characterized by altered central nervous system function or prolonged sympathetic nervous system symptoms. Forty-seven percent of the patients reported at least one reaction during the 18-mo study period, but only 4% (i.e., 6 out of 147 patients) reported severe reactions. The mean hemoglobin A1c level was significantly lower in patients who reported reactions than in patients who did not report reactions [hemoglobin A1c values (x¯ ± SEM) = 7.78 ± 0.1% vs. 9.48 ± 0.1%, respectively; P > 0.001]. The severity of hypoglycemia was inversely related to the degree of altered blood glucose control; episodes of frequent or severe symptomatic hypoglycemia occurred almost exclusively in patients with well-controlled diabetes as reflected in their near-normal hemoglobin A1c levels. There were no significant differences in mean insulin dose/kg, age, or duration of diabetes comparing patients in the four hypoglycemic categories. The results indicate that the hemoglobin A1c level can be a useful clinical guide to identify patients who are most likely to develop serious symptomatic hypoglycemia.
Absorption Kinetics and Biologic Effects of Subcutaneously Injected Insulin Preparations
Authors: Berger M , Cüppers H J , Hegner H , Jörgens V , Berchtold P
Published: March 2007

This paper describes systematic studies on the absorption kinetics of exogenous insulin from its subcutaneous tissue depot in 52 male nonobese volunteers (age 20–30 yr). Five experimental protocols were used: (1) effect of changing injection site, (2) effect of temperature change and local massage, (3) effect of aprotinin and human serum, (4) effect of mixing regular insulin with long-acting insulin preparations, and (5) effect of temperature change, muscular exercise, and local massage on the absorption of longacting insulin preparations. The fastest absorption of insulin occurred at the abdominal injection. Absorption after arm injection was faster than after thigh injection. A hot bath and local massage dramatically increased serum insulin levels in the first 90 min after injection; in contrast, a cold bath delayed absorption substantially. Both aprotinin and the subjects' own blood serum mixed with insulin caused a marked acceleration of the insulin absorption process. Absorption kinetics of two neutral regular insulins (Actrapid and Leo Regular) were virtually identical. Mixing Actrapid with Monotard caused higher serum insulin levels than the mixture of Leo Regular with NPH. A time lag of 5 min between the mixing of Actrapid and Monotard and the injection caused a delayed rise of serum insulin levels; in contrast, this delay could not be observed when Leo Regular and NPH were mixed. Volunteers performed bicycle exercise, applied a hot water bottle to the injection site, or rubbed the injection site 2 1/2 h after injection of long-acting insulin. Accelerated absorption of insulin was only observed after local massage of the injection site of Monotard, Leo NPH, and Mixtard. Local heat had no effect. Exercise caused only an increased absorption of insulin after the Mixtard injection but not after Monotard or NPH injection. These findings have clinical significance and should not be without potential benefit in the attempt to improve metabolic control in insulin-treated diabetic patients.
Insulin Delivery Systems: Do They Need a Glucose Sensor?
Authors: Albisser A M
Published: March 2007

New systems are being developed for continuous insulin infusion in diabetes mellitus. Of these, the bedside closed-loop system (artificial B-cell) normalizes measured blood glucose in the fasting and fed states, while favorably altering other fuel substrates and hormone levels in short-term studies of 1–2 days. More recent portable, external open-loop insulin delivery systems have been developed which can be programmed to achieve similar results in long-term studies in animals and humans. This is accomplished without the need for continuous glucose sensing. The partial metabolic normalization achieved is not compromised by physical exercise, and unacceptably low blood glucose levels are rarely observed. Further development and application of these new systems will enable researchers to establish whether the achievement of ideal metabolic control in diabetes can be realized with or without sensors for glucose or other metabolites.
A Miniature Glucose Sensor, Implantable in the Blood Stream
Authors: Kondo Tatsumei , Ito Katsuki , Ohkura Kunitoshi , Ito Kaname , Ikeda Shoichiro
Published: March 2007

We have developed a miniature glucose sensor using an oxygen electrode with a glucose oxidase membrane. The special character of this sensor is that the electrodes can be placed in a blood vessel and can measure the glucose level directly from the arterial blood stream if placed into an external A-V shunt. Its second notable characteristic is that the enzyme membrane is covered with a semipermeable membrane, which partially allows passage of glucose but only sufficient oxygen. This sensor is able to respond to glucose concentrations of up to 700 mg/dl in blood. This sensor loses 10% of its activity at about 200 h of continuous use, and 30% after 400 h of use. While the sensor cannot be sterilized by conventional mechanical or gas methods, certain antibiotics can be used for sterilization. To shorten the response delay of the sensor during the decreasing phase of glucose concentration, a thinner membrane is under development.
Fabrication of Miniature PO2 and pH Sensors Using Microelectronic Techniques
Authors: Liu C C , Neuman M R
Published: March 2007

Miniature PO2 and pH sensors can be used in combination with enzymatic catalysts such as glucose oxidase and glucose dehydrogenase as the basis for the development of a small glucose sensor. The applications of microelectronic techniques such as photolithography techniques and thick- and thin-film metallization are novel approaches in fabricating highly uniform and reproducible sensors that are relatively simple to calibrate and operate.
How Fibroblasts and Giant Cells Encapsulate Implants: Considerations in Design of Glucose Sensors
Authors: Woodward Stephen C
Published: March 2007

Implanted sensors ideally should measure glucose in an extracellular fluid that closely reflects changing concentrations of glucose in plasma; yet fibroblasts, fibrocytes, collagen, and giant cells provide adherent, impermeable, avascular barriers when they encapsulate irregularly-surfaced implants. Thus, sensor design should seek to provide a surface configuration that is without anchoring points for encapsulating cells, a consideration not unlike those posed in developing a nonthrombogenic surface. Examples of well-characterized host responses to various surface configurations are provided to illustrate how surface design features can avoid evoking a barrier of collagen as the host response to the sensor.
Lack of Effect of Improved Glycemic Control on C-Peptide Secretion in Patients Without Residual B-Cell Function
Authors: Seigler Deborah E , Reeves Michael L , Skyler Jay S
Published: March 2007

Ten patients with insulin-dependent diabetes mellitus underwent a program of intensification of therapy that resulted in marked improvement in glycemic control. C-peptide secretion in response to a test meal and to an intravenous glucagon challenge was used to assess pancreatic B-cell function in terms of residual endogenous insulin secretion. Patients, who had diabetes for a mean (±SEM) of 8.4 ± 1.9 yr, had minimal or no C-peptide response at baseline evaluation. C-peptide responses remained unchanged when reassessed after 2, 4, and 6 mo of improved glycemic control.
Metabolic Control in 131 Juvenile-onset Diabetic Patients as Measured by HbA1c: Relation to Age, Duration, C-Peptide, Insulin Dose, and One or Two Insulin Injections
Authors: Dahlquist G , Blom L , Bolme P , Hagenfeldt L , Lindgren F , Persson B , Thalme B , Theorell M , Westin S
Published: March 2007

Glycosylated hemoglobin A (HbA1c), considered to reflect long-term metabolic control of diabetes, was analyzed in 131 patients, aged 2 5/12–19 6/12 yr, with juvenile-onset diabetes. Using stepwise multiple regression HbA1c, fasting blood glucose and plasma 3-hydroxybutyrate were analyzed as dependent variables versus independent variables such as age of the patients, duration of the disease, level of plasma immunoreactive C-peptide (IRCP), insulin dose, and number of insulin injections (one or two) per day. HbA1c was inversely related only to IRCP concentration. A low but significant, positive correlation was found between HbA1c and the duration of diabetes. Stepwise addition of the other independent variables did not further increase the fraction of explained variance. HbA1c was also correlated with a subjective rating score of the metabolic control performed by the treating physician. Fasting plasma glucose was significantly related to HbA1c but not to any of the independent variables. Fasting 3-hydroxybutyrate showed an inverse correlation to the age of the patient. The present study showed that in juvenile-onset diabetic patients, endogenous insulin secretion as reflected by IRCP was the factor best correlated with a low level of HbA1c. After the cessation of endogenous insulin secretion, there is a progressive deterioration of metabolic control and multiple injections of insulin rather than one or two per day may be needed to reach optimal control in the patients.
Induced Basal Normoglycemia and Altered Platelet Aggregation in Non-insulin-dependent Diabetes
Authors: Evans R J , Lane J , Holman R R , Turner R C
Published: March 2007

Non-insulin-dependent diabetic subjects had abnormally raised in vitro platelet aggregation rates to collagen or ristocetin when thought to be “well-controlled” on diet alone but shown to have raised basal plasma glucose levels. Basal normoglycemia, induced with either ultralente insulin or chlorpropamide, was associated with a significant reduction of the enhanced platelet aggregation rates to normal. Some sulfonylurea drugs have been reported to have specific anti-platelet aggregatory properties, but the degree of plasma glucose control is probably more relevant.
C-Peptide
Authors: Hoekstra J B L , van Rijn H J M , Erkelens D W , Thijssen J H H
Published: March 2007

C-peptide is a polypeptide originating from proinsulin after its cleavage in the B-cell. It is secreted equimolarly with the other cleavage product, insulin, into the portal circulation. Only a minimal fraction of C-peptide is extracted by the liver; it is supposed to be mainly removed by the kidney. A small, constant proportion is excreted in the urine. C-peptide is measured in serum and urine by radioimmunoassay. The major sources of error of the assay are related to standard, tracer, antiserum specificity and reactivity with proinsulin, and to degradation of C-peptide. Many secretagogues are used to evaluate the B-cell function, of which glucagon is the most simple. Clinical applications of C-peptide include differentiating between endogenous and exogenous hyperinsulinism and establishing the need of insulin therapy in diabetic patients already treated with insulin. The primary value of C-peptide, however, is in clinical research, where it offers a unique opportunity to follow the B-cell secretion in diabetic subjects and to evaluate the difference that various factors may exert on its activity.
C-Peptide Reactivity as a Measure of Insulin Dependency in Obese Diabetic Patients Treated with Insulin
Authors: Hoekstra Joost B L , Van Rijn Herman J M , Thijssen Joseph H H , Erkelens D Willem
Published: March 2007

The C-peptide increase after an oral glucose tolerance test (OGTT) and intravenous glucagon test (GT) was assessed to establish actual insulin dependency in 16 obese diabetic patients treated with insulin for years. The results, compared to five reference groups, showed two types of reaction: first, a negative response in 3 patients with a minimal C-peptide increase after either stimulation (range 0–0.1 ng/ml during GT, 0–0.5 during OGTT), not different from that in the insulin-dependent reference group (GT: 0.1 ± 0.2, OGTT: 0.1 ± 0.3. x¯ ± SD). Second, a positive response in 13 patients with a C-peptide increase, different from that in the insulin-dependent group after glucagon (range 0.7–5.6), and in 6 patients after OGTT (range 0.8–1.8). When insulin treatment was discontinued in two nonresponders, the B-hydroxybutyrate levels and ketobutyrate levels increased to over 2.1 and 0.60 mmol/L within 10 days, proving insulin dependency, and thus type I diabetes. B-hydroxybutyrate and ketobutyrate levels increased to maximal 0.4 and 0.17 after stopping insulin therapy in nine positive responders. No ketoacidosis developed during a 4-wk follow-up, indicating non-insulin dependency (type II diabetes). Measuring C-peptide after glucagon is a simple test that may be a discriminative method to establish insulin dependency in obese diabetic patients treated with insulin.
Improvement of Lipid Status in Diabetic Boys: The 1971 and 1979 Joslin Camp Lipid Levels
Authors: Blanc Marc H , Ganda Om P , Gleason Ray E , Soeldner J Stuart
Published: March 2007

Since 1972, young type I diabetic patients seen by Joslin Clinic physicians have been advised to use a low cholesterol diet with a high proportion of polyunsaturated fat. Mean fasting cholesterol and triglyceride levels at admission to the Joslin Boys Camp for the years 1971 (N = 129) and 1979 (N = 79) were compared. In 1979, the mean cholesterol level was lower by 44 mg/dl (P < 0.001) and the mean triglyceride by 21 mg/dl (P < 0.001) compared with 1971. The incidence of hyperlipoproteinemia decreased from 21.6% to 7.6% with a complete disappearance of types IV and V during the same period. A decrease in the development of arteriosclerotic cardiovascular diseases in type I diabetic patients might be anticipated from this diet modification.
Association of Type I (Insulin-dependent) Diabetes Mellitus, Autoimmunity, Antinuclear Antibody, and Membranoproliferative Glomerulonephritis
Authors: Srikanta S , Malaviya A N , Rajagopalan P , Bhuyan U N , Ahuja M M S
Published: March 2007

In a large series of patients with insulin-dependent diabetes mellitus who were screened for autoantibodies, two patients were positive fot antinuclear antibodies. Both of these patients developed severe renal disease with the renal biopsy findings of membranoproliferative glomerulonephritis. Multiple autoantibodies and circulating immune complexes were demonstrated in their sera. There was evidence suggesting complement consumption. This article illustrates that immune complex glomerulonephritis can occur in some patients with IDDM, particularly in those with antinuclear antibody and polyendocrine involvement, and that renal biopsy in such cases may have prognostic and therapeutic importance.
Normalization of Fasting Blood Glucose Levels in Insulin-requiring Diabetes: The Role of Ethanol Abstention
Authors: Feingold Kenneth R , Siperstein Marvin D
Published: March 2007

The long-term remission of insulin-dependent diabetes mellitus is an unusual occurrence. The present report describes three cases of typical insulin-dependent diabetes in which the metabolic abnormalities greatly improved after the patients abstained from excessive ethanol intake. Our patients presented with polyuria, polydipsea, and weight loss of several weeks duration and laboratory studies revealed marked elevations in blood glucose concentrations and, in two of the three patients, mild ketosis. When these patients subsequently abstained from excessive ethanol intake, the elevations in blood glucose levels and the clinical symptoms of diabetes resolved. Two of our three patients have a strong family history of diabetes mellitus and we have therefore hypothesized that excessive ethanol intake only results in hyperglycemia in individuals with either an underlying predisposition to develop diabetes or mild unrecognized preexisting diabetes. It is important that clinicians recognize that excessive ethanol intake can lead to hyperglycemia and that abstention from ethanol may result in the marked improvement of the metabolic abnormalities.
Nadirs of Oral Glucose Tolerance Tests Are Independent of Age and Sex
Authors: Lev-Ran Arye
Published: March 2007

We analyzed nadirs of 75-g oral glucose tolerance tests in 400 subjects who remained completely asymptomatic during the test. The median nadir was 63 mg/dl, the 10th percentile 48 mg/dl, and the 2.5th percentile 41 mg/dl. Seventy-five percent of the nadirs occurred at 3–4 h. There were no differences in the absolute level of nadirs between men and women, nor between the subjects 17–30 and 61–74 yr of age.
Influenza Immunization in Adults with Diabetes Mellitus
Authors: Feery Brian J , Hartman Leonard J , Hampson Alan W , Proietto Joseph
Published: March 2007

The antibody responses to influenza vaccination of a group of adult diabetic patients were compared with responses in a healthy group of regular volunteer vaccinees. The initial and final geometric mean hemagglutination-inhibiting antibody titers were lower in the patient group, but the relative increase in titers was greater for each of the vaccine components. The percentage of fourfold rises in individual titers was greater in the diabetic group than in the control group. It was concluded that patients with diabetes mellitus responded normally to influenza vaccination. This was confirmed in an additional study. There was no significant difference in the antibody responses of patients treated with insulin or oral antidiabetic agents. There was no impairment of diabetic control as a result of influenza vaccination when this was evaluated by measuring the concentration of glycosylated hemoglobin, or by random blood glucose estimations. There was no significant change in the serum insulin level after immunization in patients on oral diabetic agents. It was concluded that influenza vaccination was safe and effective in adult diabetic patients.
Diabetes Mellitus and Thyroid Disease
Authors: Mouradian Maral , Abourizk Nicolas
Published: March 2007

Diabetes mellitus not infrequently coexists with hypo- and hyperthyroidism. Hyperthyroidism aggravates glucose intolerance. A review of this phenomenon reveals multiple mechanisms, which include increased hexose intestinal absorption, decreased responsiveness to insulin, and increased glucose production. Conflicting results are obtained when circulating insulin level is measured in thyrotoxicosis. The role of glucagon and a-cell sensitivity is unclear. Diabetes mellitus influences the assessment of thyrotoxicosis by falsely decreasing the blood levels of thyroxine (T4) and triiodothyronine (T3) during severely uncontrolled hyperglycemia. Hypothyroidism is found in about 3% of patients with insulin-dependent diabetes mellitus (IDDM). Moreover, 13–20% of IDDM patients have elevated blood thyrotropin levels and anti-thyroid antibodies. Hypothyroidism per se seems to ameliorate hyperglycemia. A subtype of IDDM shares similar immunogenetic features with familial autoimmune thyroiditis. Studies of IDDM probands who show a high prevalence of circulating thyroid antibodies reveal the presence of such antibodies in their first-degree relatives. Circulating islet-cell antibodies, detected in a majority of IDDM patients at the onset of their disease, tend to persist only in those patients with coexistent polyendocrine autoimmune disease, including thyroiditis. Similar human leukocyte antigen (HLA) locus types are associated with thyroiditis and IDDM, namely HLA-Dr3 and -Dr4.