Mean Glycemia Research Articles

Biological Variation of Glycohemoglobin

Glycohemoglobin (GHb) is a measure of long-term mean glycemia that predicts risks for the development and/or progression of diabetic complications in patients with type 1 and type 2 diabetes (1)(2). Several reports have suggested, however, that although the within-subject variation in GHb unrelated to glycemia is minimal, there is substantial between-subject variation in GHb, e.g., “low glycators” and “high glycators” (3)(4)(5). These reports have suggested that because of this large between-subject variation, GHb may not be useful for diabetes screening or diagnosis and that when GHb is used for routine management of patients with diabetes, different patients may require very different GHb target values to achieve the same overall glycemic status. We therefore examined the biological variation of GHb and fasting plasma glucose (FPG) in nondiabetic individuals. Individuals without diabetes (n = 48) participated in a study of an artificial sweetener that has no effect on GHb or plasma glucose concentrations [Submission to Food and Drug Administration. McNeil Specialty Products Company food additive petition 7A3987 (Sucralose), 1987–1997]. Because the study was designed to detect minimal changes in plasma glucose concentrations, all participants were men to avoid the effects of cyclic hormonal changes on insulin (and therefore, plasma glucose) concentrations. At the prestudy screening, all individuals were healthy on the basis of a medical history, physical examination, and electrocardiography results; results of hematology and blood chemistry studies, urine examination, and measures of blood …

Glycated hemoglobin: a useful post-mortem reference marker in determining diabetes

Glycated hemoglobin (HbA1c) has been demonstrated to be a useful marker for long-term glucose control in diabetes. This parameter characterizes each non-enzymatic fixation of glucose on hemoglobin. It is a useful test in addition to periodic glycemia controls since it reflects the mean glycemia of the past 60 days. We studied the conservation of HbA1c at 4°C as a function of time with different anti-coagulants and preservatives (3, 6 months, 1 year). A total of 106 tests were performed using the high performance liquid chromatography (HPLC) method dedicated to the semi-automatic analysis of HbA1c (Bio-Rad®) and we applied the method in forensic cases. Conservation at 4°C was good for as long as 3 months in blood samples collected with fluoride and 6 months in samples collected in a dry or in a heparinized tube. In non-diabetic subjects, HbA1c reference values obtained from forensic samples were identical to those of living controls (3.5–6.25% of total hemoglobin). All positive HbA1c results were confirmed by a medical evaluation. This method was successfully applied to five forensic cases. In cases of increased acetonemia, acetone or isopropanol are easily measured. However, in some unexplained post-mortem circumstances, increased HbA1c permits to differentiate alcoholic or starvation ketoacidosis from the diabetic cases. Glycated hemoglobin should, therefore, be considered the forensic marker of choice in the post-mortem diagnosis of a diabetic disorder and demonstrates its usefulness in post-mortem validation.

CPAP treatment does not affect glucose–insulin metabolism in sleep apneic patients

Objective: We investigated glucose metabolism and insulin resistance in non-obese and moderately overweight sleep apnea patients, as well as their response to nasal CPAP treatment. Methods: A group of subjects with glucose intolerance was screened for sleep disordered breathing by clinical interview and ambulatory recordings. Ten subjects were found to have untreated sleep apnea and were asked to participate in further investigation. This included nocturnal polysomnography, oral glucose tolerance test and indirect calorimetry. Subjects then had calibration of nasal CPAP with polysomnography. Two months after start of treatment, all subjects were restudied as at baseline. In parallel, six obstructive sleep apnea syndrome (OSAS) subjects, diagnosed through the sleep clinic, were matched for gender, age and oxygen desaturation index with the other group, and had a euglycemic hyperinsulinemic clamp at baseline and after 2 months of nasal CPAP. Results: The first ten patients showed no change in total glucose oxidation, glucose oxidation by weight or by fat free mass, or insulin energetic expenditure, despite nocturnal usage of nasal CPAP. Similarly, when comparing baseline to the treatment at 2 months, the six OSAS patients had no change in mean glycemia, insulin, C peptide and hemoglobin (Hgb) A1C measurements. No difference in the amount of glucose infused during the duration of the clamp was noted either. Conclusion: Our data do not support the existence of a significant relationship between glucose and insulin metabolism and obstructive sleep apnea. Obesity, when present, is the important variable.

Effects of dietary lipids on renal function of aged rats.

Normal aging is accompanied by renal functional and morphological deterioration and dietetic manipulation has been used to delay this age-related decline. We examined the effects of chronic administration of diets containing 5% lipid-enriched diet (LD, w/w) on renal function of rats at different ages. Three types of LD were tested: canola oil, fish oil and butter. Mean systemic tail-cuff blood pressure and glycemia remained within the normal range whatever the age and the diet of the animals. Proteinuria began to rise from the 8th month in the groups ingesting LD, while in the control group it increased significantly (above 10 mg/24 h) only after the 10th month. With age, a significant and progressive decline in glomerular filtration rate (GFR) and renal plasma flow was observed in the LD groups but after 6 months of lipid supplementation, the decline in these parameters was more marked in the butter and fish oil groups. By the 18th month, the lowest GFR level was observed in the group ingesting the butter diet (2.93 +/- 0.22 vs 5.01 +/- 0.21 ml min(-1) kg(-1) in control, P<0.05). Net acid excretion, evaluated in 9- and 18-month-old rats, was stimulated in the fish oil group when compared both to control and to the other two LD groups. These results suggest that even low levels of LD in a chronic nutritional regimen can modify the age-related changes in renal function and that the impact of different types of lipid-supplemented diets on renal function depends on the kind of lipid present in the diet.

Nateglinide reduces mean glycemia in diet- and previously treated type 2 diabetic patients

Nateglinide reduces mean glycemia in diet- and previously treated type 2 diabetic patients

Cytochrome P450 2E1 activity in diabetic and obese patients as assessed by chlorzoxazone hydroxylation.

Cytochrome P450 2E1 (CYP2E1) is a phase I detoxification enzyme, which is induced by chronic alcohol consumption. It is involved in the activation of numerous carcinogens and in the production of free radicals. As it has previously been shown to be induced in diabetic and obese rats, the aim of this study was to investigate its induction level in poorly-controlled diabetics and in obese patients (Body Mass Index > 30 kg/m2). CYP2E1 activity was determined in 35 diabetic and 17 obese patients by using the in vivo chlorzoxazone hydroxylation test. Even though the glucidic parameters were highly disturbed (mean fasting glycemia > 7.9 mmol/L, post prandial glycemia > 12.2 mmol/L and fructosamine > 326 mumol/L), CYP2E1 activity was not enhanced either in insulin-dependent diabetics (IDDs, n = 7) nor in non-obese non-insulin-dependent diabetics (NIDDs, n = 15) when compared to controls (n = 42) (0.21 +/- 0.03, 0.33 +/- 0.03 and 0.30 +/- 0.02, respectively, mean +/- SEM). However, this activity was lower in IDDs when compared to NIDDs (P < 0.05). In obese patients, with (n = 13) or without (n = 17) NIDD mellitus, CYP2E1 activity was increased by a mean of 40% when compared to controls. In addition, positive correlations were found in all subjects (controls or patients, n = 74) between CYP2E1 activity and serum cholesterol (r = 0.42, P < 0.0001), triglycerides (r = 0.44, P < 0.0001) and BMI (r = 0.36, P < 0.001). Accordingly, subjects with cholesterol and/or triglyceride serum levels above 6.4 and 1.8 mmol/L, respectively, displayed a mean increase of 40% of their CYP2E1 activity vs subjects within the above values. It is believed that individuals with increased CYP2E1 activity are more susceptible to the adverse effects of CYP2E1-mediated activation of toxins and carcinogens.

Repercusiones autonómicas y metabólicas en un modelo experimental de isquemia cerebral global y focal

During the last decades the influence of cerebrovascular disease on heart and autonomic nervous system has been studied in numerous reports. Autonomic and metabolic changes have been described during brain ischemia. We studied some parameters and its modifications during global (GBI) and focal brain ischemia (FBI). Ten Wistar rats were subjected to global ischemia and eleven to focal brain ischemia, during 20 and 90 minutes followed in both cases by reperfusion. Mean blood pressure, heart rate and glycaemia before, during and after brain ischemia were registered. pH, pO2 and pCO2 were maintained within normal range using endovenous tamponed solutions. During GBI the blood pressure rose and returned to normal in the reperfusion period. Heart rate decreased in both stroke models and hyperglycaemia was present from the beginning in two groups. GBI and FBI bring about autonomic changes as increased mean blood pressure (only in GBI) and decreased heart rate; probably these might be explained by an autonomic nervous system disorder or by intracranial hypertension. Hyperglycaemia could be related to cathecholamines secretion. These effects might influence in the pathophysiology of brain ischemia.

Glycosylated hemoglobin and fructosamines: does their determination really reflect the glycemic control in diabetic patients?

The present experiment was designed to determine whether scavenging capacity of serum, in addition to glucose level, influences hemoglobin and serum protein glycosylation in non-insulin dependent diabetic patients. For this purpose fortyseven patients homogeneous for age, disease duration, therapy and glyco-metabolic control were selected Fasting and post-prandial glycemia and insulinemia as well as glycosuria were weekly analysed during the sixty days preceding glycosylated hemoglobin (HbA1c), fructosamines and serum scavenging capacity determination. This last parameter has been evaluated by a method based on the property of β-phycoerythrin (β-PE) to loss its fluorescence when damaged by oxygen radicals, that were produced by Cu ++ and H 2C 2. The oxygen radical absorbance capacity (ORAC OH) of serum was assayed as the ability of serum to delay the loss of β-PE fluorescence. As expected, a statistically significant positive correlation was found comparing both fructosamines and HbA1c levels with mean fasting glycemia measured over twenty and sixty days, respectively. The key result of this study is represented by the finding that both HbA1c and fructosamines levels show a statistically significant negative correlation with ORAC OH values. This correlation can explain a large percent of the data dispersion occurring when ORAC OH is not taken into account. In order to better describe the role of ORAC OH, patients were separated into two sub-groups with an ORAC OH lower (L-ORAC OH) and greater (H-ORAC OH) than 100 U/ml. Examining the correlation between mean fasting glycemia and the two glycosylated proteins considered in these two sub-groups, curves with different slopes were obtained, supporting that the rate of glycosylation of both proteins was higher in L-ORAC OH patients as compared to those with HORAC OH. Present data suggest that for a proper interpretation of the HbA1c and fructosamines data in diabetic patients, the scavenging capacity level of serum should be taken into account

Longitudinal Doppler Ultrasound Assessment of Fetal Circulation in Diabetic Pregnancies in Relation to Maternal Glycemic Control

In order to determine the influence of maternal glycemic control on the fetal circulation, Doppler flow velocity waveforms (DFVWs) were obtained at 30, 33, and 36–40 weeks in 17 women with overt diabetes, 20 with gestational diabetes (GDM), and 14 low-risk pregnant women. DFVWs were obtained from the umbilical artery (UA), internal carotid artery (ICA), ascending aorta, and main pulmonary artery. The ICA resistance index was lower in GDM than controls (P = 0.014). As a result, the cerebral-umbilical Doppler ratio (ICA resistance index/UA resistance index) was lower in GDM than controls (P = 0.031). There was a significant correlation between either the mean daily glycemia (r = 0.54, P < 0.01) or the mean daily M-value, an index of glucose excursion and mean glycemia (r = 0.61, P< 0.001), and the cerebral-umbilical Doppler ratio. As the maternal glycemic control became tighter, the fetal cerebral-umbilical Doppler ratio decreased to values similar to the “brain-sparing” effect described in growth-retarded ...

Insulin and satiety from feeding in pancreatic-normal and diabetic rats

Insulin's role in food ingestion and satiety was investigated in streptozotocin-diabetic and pancreatic-normal rats. Markedly diabetic rats (60–65 mg/kg b.wt. streptozotocin with mean glycemia of 380 mg/dl) were observed for daily food/water intake and body weight changes and meal pattern in a standard operant chamber. Diabetic animals showed an immediate hypophagia (days 1–4) by decreasing meal size (MS). As animals lost weight, a significant hyperphagia appeared, accomplished by an elevation in MS. Treatment with insulin infused via osmotic minipump at a stable rate (6.0 U/24 h) reduced polyuria and glycemia, eliminated glycosuria, and restored weight gain. MS did not, however, return to baseline immediately. In a second experiment with milder diabetes (20–22 mg/rat streptozotocin, which produced glycemia ranging from 148 to 304 mg/dl), significant hyperphagia appeared, again attributable to an increase in MS. Minipumps infusing 2.4–4.0 U insulin/24 h reversed this hyperphagia. In pancreatic-normal rats, pumps infusing insulin at 1.2 or 2.4 U/24 h produced a modest hypophagia accomplished by a primary decrease in nocturnal intake (11% suppression in dark feeding). Subdiaphragmatically vagotomized rats showed an attenuation of this suppression (no significant effects on food or water intake produced by insulin infused). Insulin appears to participate in satiety by limiting MS, without significantly shortening latency to take the next meal.

THE ENDOCRINE PANCREAS IN BRAIN-DEAD DONORS A PROSPECTIVE STUDY IN 25 PATIENTS

To determine whether hyperglycemia in brain-dead donors is a sign of endocrine pancreas insufficiency, we studied pancreatic function in 25 consecutive brain dead patients. Blood samples were drawn at 2-hr intervals from donor referral until organ procurement to analyze glucose, insulin, and C-peptide levels. After donor retrieval, two specimens were taken from the pancreas for a subsequent immunohistochemical examination. At referral mean glycemia was 13.60 +/- 1.49 mmol/L, and there was a large range of plasma glucose levels (4.6-31.6). Of 25 patients, 16 had glycemia above 10 mmol/L. At organ procurement a mean of 20 hr later, mean glycemia as 8.61 +/- 0.58 mmol/L (P < 0.005 with paired t test), and only 5 patients had glycemia above 10 mmol/L. Hyperglycemia was associated with elevated insulin and C-peptide levels during donor management. An elevated C-peptide/glucose molar ratio might be considered a sign of peripheral insulin resistance. Hyperglycemia above 25 mmol/L could not be related to the amount of glucose administered during donor maintenance. Severe hyperglycemia had a natural tendency to be partly corrected. Histologic and immunohistochemical examinations were available in 17 cases and can be considered normal. It is concluded that endocrine pancreatic function can be considered effective after brain death. The mechanism of the relative insulin resistance of these patients requires further study. Blood glucose levels, in the range observed in this study, are not a good donor criterion of endocrine pancreatic function before pancreas transplantation.

In vitro secretion of interleukin-1β and interferon-γ by peripheral blood lymphomononuclear cells in diabetic patients

There is evidence that cytokines, in particular interleukin-1β (IL-1gb) and interferon-γ (IFN-γ) might mediate β cell destruction in type 1 diabetes. Therefore the secretion of these cytokines by peripheral blood lymphomononuclear cells (PBMNC) was investigated in basal conditions and 48 h after stimulation with T-cell mitogen phytohaemagglutinin (PHA) in 33 diabetic patients and in 10 normal controls. The patients were divided in 4 groups (Group 1, 10 controls; Group 2, 13 newly diagnosed type 1 diabetics, the onset had occurred from 5 days to 3 months before the study; Group 3, 10 Long Standing (LS) type 1 diabetics with duration of the disease between 2 years and 10 years; and Group 4, 10 type 2 diabetics). No difference was found among the 4 groups considered in IL-1β secretion by unstimulated cultures, although the percentage of TAC+ cells was significantly higher in type 1 newly diagnosed diabetic patients with respect to the LS, the type 2 diabetics and the controls. After PHA stimulation a significant increase of IL-1β was found in newly diagnosed type 1 diabetic patients in comparison with the control subjects, the LS and type 2 diabetic patients ( P < 0.001). The supernatants of newly diagnosed type 1 diabetics also showed a significant reduction in IFN-γ production both in basal ( P < 0.01) and in stimulated conditions ( P < 0.001) in comparison with the controls, the LS ( P < 0.002 in basal, and P < 0.001 in stimulated conditions) and the type 2 diabetic patients ( P < 0.001 both in basal and stimulated conditions). No correlation was found between lymphokine production levels and age, sex and metabolic control parameters, i.e daily mean glycemia and HbA 1c levels. Our data suggest a dysregulation in the lymphokine cascade in the diabetic disease, restricted to the early stage of type 1 diabetes.

Blood or Urine Glucose-Based Insulin Therapy and Control of Glycemia: Computer-Simulation Study

Adjustment algorithms for conventional insulin therapy must be tested for safety and efficacy before clinical implementation. We did this by computer simulation. Accordingly, a computer simulator of human intermediary metabolism created 10 randomly chosen diabetic subjects for study. All were well defined with respect to compliance (i.e., medication and diet) and life-style (i.e., physical and emotional stress). Insulin-adjustment algorithms that were tested calculated daily insulin dosages for these computer-simulated patients based on either blood or urine glucose concentrations self-measured 4 times/day before breakfast, lunch, dinner, and bedtime snack. The twofold purpose of the simulation study was to determine the ability of the adjustment algorithms to improve initially poor metabolic control and to compare the outcomes when either blood or urine glucose measurements were the basis on which glycemic control was implemented. A significant improvement in metabolic control could be achieved with either blood or urine glucose measurements as input to the algorithms. Detailed comparisons between blood and urine glucose-based treatments showed no significant advantage of blood glucose-based algorithms at breakfast (122 +/- 21 vs. 131 +/- 16 mg/dl) and dinner (117 +/- 27 vs. 130 +/- 23 mg/dl), whereas mean glycemia at lunch (122 +/- 24 vs. 164 +/- 21 mg/dl) and bedtime (117 +/- 25 vs. 150 +/- 21 mg/dl) after 120 days of simulation did differ significantly (P less than 0.01). Hypoglycemia was not provoked by either treatment. Total daily insulin doses evolved by blood glucose-based algorithms were significantly (P less than 0.05) higher than the doses used by urine glucose-based algorithms (53 vs. 47 U).(ABSTRACT TRUNCATED AT 250 WORDS)

Continuous Ambulatory Peritoneal Dialysis (CAPD) in a Patient with Glucose-6-Phosphatase Deficiency

The metabolic disturbances in glucose-6-phosphatase deficiency (von Gierke's disease) are the consequence of hypoglycemia, occurring mostly during the night. Continuous provision of glucose is the aim of every recently introduced treatment procedure. We studied the influence of continuous ambulatory peritoneal dialysis (CAPD) on the metabolic disturbances in a 42-year-old female patient with von Gierke's disease and end-stage renal disease. During six months of CAPD, there were no dialysis-related complications. The metabolic acidosis didn't worsen: arterial bicarbonate and lactate were not changed. Mean glycemia was 118.6 +/- 14.4 mg%. Total lipemia, cholesterol and triglycerides were not different from those before CAPD, despite the fact that all hypolipidaemic drugs were stopped. Three different exchange procedures were compared during the night: no dialysis, one exchange with a 2 L solution without buffer containing glucose 15 g/L and containing glucose 42.5 g/L. The results show that the 4.25% glucose solution prevents hypoglycaemia, and diminishes the increase in lactate and pyruvate concentration. Intraperitoneal glucose normalizes the plasma free fatty acid concentration. A very important result is the disappearance of hypo-insulinism. We conclude that, from a clinical point of view, CAPD is a well-tolerated treatment in von Gierke's disease. The limited results provide some evidence that the use of a 4.25% glucose solution as an overnight exchange, instead of the usual 1.5% solution, can prevent at least partly the glycogenolysis and consequently the metabolic disturbances of von Gierke's disease.

A portable system for continuous intravenous insulin delivery: characteristics and results in diabetic patients.

A portable insulin delivery system for clinical use has been developed, with the aim of improving glycemic control for prolonged periods for individuals with insulin-dependent diabetes. It weighs 1.5 kg and measures 8 × 11 × 20 cm. A plastic case contains two insulin reservoirs, two peristaltic pumps (flow variability ± 3%), a battery pack, and voltage regulator. Silastic tubes connect the reservoirs to an indwelling intravenous catheter inserted into the arm. The system is carried by a strap over the shoulder. One pump operates continuously, giving insulin at a “basal” rate, and the other is activated during meals to give a preprogrammed waveform of insulin, the latter controlled by a small bedside unit. Twelve insulin-dependent diabetic patients were infused with insulin by this system for 4–60 days (mean 18 days), for a total of 199 patient days. Insulin delivery rates were modified according to data obtained by intermittent glycemic monitoring, and on one and in some cases two days glycemia was continuously monitored (N = 10). With a basal infusion rate of 18 ± 2 mU/min (mean ± SEM), fasting glycemia was 99 ± 7 mg/dl. The mean insulin delivered with meals was 12 ± 2 U for breakfast, 9 ± 2 U for lunch, and 11 ± 2 U for dinner. Mean glycemia before lunch and supper was 102 ± 6 and 121 ± 11 mg/dl, respectively. The lowest mean glycemia occurred after lunch (88 ± 7 mg/dl) and the mean peak postprandial glycemia was 136 ± 8 mg/dl (2 h after supper). The range from lowest to highest observed value was 47–189 mg/dl. This system is capable of maintaining glycemia within the normal range for periods up to 60 days. Further refinement of the waveforms of insulin delivery may allow for total glycemic normalization. The future refinement of such a system will allow for longer-term studies addressing the relationship between glycemic control and complications.

Cholesterol metabolism in diabetes: the effect of insulin on the kinetics of plasma squalene.

The turnover of isotopically labeled squalene formed in plasma from [14C]mevalonate has been used to measure cholesterol synthesis in diabetics over a 7-h period. Five patients were studied while in poor diabetic control (mean daytime glycemia, 349 mg/dl) and at a later date once improved control was established by multiple daily insulin injections (mean glycemia, 175 mg/dl). This degree of diabetic control resulted in an increase in the fractional conversion of [14C]mevalonic acid to [14C]squalene from 55.2 +/- 1% to 67.5 +/- 4% (P less than 0.025). These data together with the area under the squalene specific activity curve yeild an estimated rate of cholesterol synthesis based on the likely assumption that mevalonate pool size did not decrease. Insulinization increased this calculated mean rate of cholesterol synthesis from 961 +/- 151 to 1206 +/- 223 mg/day (P less than 0.025). The use of squalene kinetics to evaluate changes in cholesterol synthesis deserves further study, particularly in metabolically unstable states such as diabetes in which conventional methods for measuring cholesterol synthesis are difficult to apply and to interpret.