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Effects of postmenopausal hormone replacement therapy on central abdominal fat, glycemic control, lipid metabolism, and vascular factors in type 2 diabetes: a prospective study.

OBJECTIVE: To examine the effects of hormone replacement therapy (HRT) on lipid metabolism, glycemic control, total body and central abdominal fat, blood pressure (BP), and arterial pulse wave velocity (APWV) in overweight postmenopausal females with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a 12-month prospective study of 14 subjects (mean +/- SD age 57.5+/-5.6 years, BMI 29.5+/-4.8 kg/m2) randomized to 6 months of observation or HRT before crossover. HRT consisted of 2 months of conjugated equine estrogen (CEE) 0.625 mg daily, followed by 4 months CEE and medroxyprogesterone 5 mg daily. Measures included anthropometry, fasting glucose, insulin, HbA1c, total and HDL cholesterol, triglycerides, apolipoprotein B, LDL particle size, nonesterified fatty acids (NEFA), sex hormone-binding globulin, resting energy expenditure (REE), total and central abdominal fat (by dual-energy X-ray absorptiometry), resting BP, APWV (by applanation tonometry), physical activity, well-being, and sexual function. RESULTS: Six months of HRT resulted in significant reductions in waist-to-hip ratio (-0.03+/-0.01 vs. 0.01+/-0.009, P = 0.007), HbA1c (-0.34+/-0.24 vs. 0.6+/-0.4%, P = 0.04), total cholesterol (-0.6+/-0.1 vs. 0.2+/-0.2 mmol/l, P = 0.001), central abdominal fat (-175+/-51 vs. -24+/-56 g, P = 0.05), and improved physical functioning (P = 0.05), compared with observation. There was a minor increase in REE with HRT (33+/-23 vs. -38+/-23 kJ/day, P = 0.04). Total fat mass, fasting glucose, insulin, triglyceride, apolipoprotein B, NEFA, resting BP, APWV, and physical activity were unchanged. CONCLUSIONS: Postmenopausal HRT in these overweight women with type 2 diabetes was associated with a reduction in central adiposity and improvement in lipid metabolism and glycemic control without deterioration in weight status or cardiovascular parameters measured. Whether HRT-induced improvements in these cardiovascular risk factors result in lower long-term cardiovascular morbidity and mortality, as observed in nondiabetic women, awaits further study.

Abdomen↗

Lack of change of lipoprotein (a) concentration with improved glycemic control in subjects with type II diabetes.

Recently, lipoprotein (a) [Lp(a)] has been identified as a major risk factor for coronary heart disease. No data are available on the effect of improved metabolic control on plasma Lp(a) concentrations in subjects with type II diabetes mellitus, a group at high risk for coronary heart disease. We examined the effects of improved metabolic control on plasma lipid and lipoproteins and Lp(a) concentrations in 12 subjects before and after 21 days of tight metabolic control. Glycosylated hemoglobin declined from 8.9% to 6.9% (P less than .002). Lp(a) increased slightly from 21.4 to 25.8 mg/dL (P = .119) with improved metabolic control. There were no significant differences in total, low-density, or high-density cholesterol values, although the decline in triglyceride concentrations was statistically significant. The distribution of apolipoprotein (a) [apo (a)] isoforms in subjects with type II diabetes mellitus was not unusual and the apo (a) isoform patterns did not change with improved metabolic control. Although the number of subjects was small, there was no decline in Lp(a) concentrations with improved control and thus the effect of glycemic control on Lp(a) concentrations may be much smaller in type II than in type I diabetes. These results suggest that diabetic subjects with elevated Lp(a) concentrations should have intensive management of conventional cardiovascular risk factors such as high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), and blood pressure.

Blood Glucose↗

Health and economic impact of combining metformin with nateglinide to achieve glycemic control: Comparison of the lifetime costs of complications in the U.K.

BACKGROUND: To reduce the likelihood of complications in persons with type 2 diabetes, it is critical to control hyperglycaemia. Monotherapy with metformin or insulin secretagogues may fail to sustain control after an initial reduction in glycemic levels. Thus, combining metformin with other agents is frequently necessary. These analyses model the potential long-term economic and health impact of using combination therapy to improve glycemic control. METHODS: An existing model that simulates the long-term course of type 2 diabetes in relation to glycosylated haemoglobin (HbA1c) and post-prandial glucose (PPG) was used to compare the combination of nateglinide with metformin to monotherapy with metformin. Complication rates were estimated for major diabetes-related complications (macrovascular and microvascular) based on existing epidemiologic studies and clinical trial data. Utilities and costs were estimated using data collected in the United Kingdom Prospective Diabetes Study (UKPDS). Survival, life years gained (LYG), quality-adjusted life years (QALY), complication rates and associated costs were estimated. Costs were discounted at 6% and benefits at 1.5% per year. RESULTS: Combination therapy was predicted to reduce complication rates and associated costs compared with metformin. Survival increased by 0.39 (0.32 discounted) and QALY by 0.46 years (0.37 discounted) implying costs of pound 6,772 per discounted LYG and pound 5,609 per discounted QALY. Sensitivity analyses showed the results to be consistent over broad ranges. CONCLUSION: Although drug treatment costs are increased by combination therapy, this cost is expected to be partially offset by a reduction in the costs of treating long-term diabetes complications.

Journal Article↗

Kidney functions in newly diagnosed type 2 diabetic subjects: role of glycemic control.

BACKGROUND: The increased urinary albumin excretion (UAE) found at the diagnosis in type 2 diabetes may at least be functional and, thus reversible, as in type 1 diabetes. Furthermore, a positive correlation has been found between the glycemic control and UAE in type 2 diabetic subjects. MATERIAL AND METHODS: The impact of glycemic control after achieving three months of continuous normo-glycemia was studied in 26 (including 16 males and 10 females) newly diagnosed type 2 diabetic patients to assess renal size/volumes, various renal functions and UAE. RESULTS: A significant reduction was seen in glomerular filtration rate (GFR), UAE and fractional albumin clearance after achieving near normoglycemia (p < 0.01). A decrease in the kidney size/volume, though statistically insignificant, was also observed. Besides a decline in GFR of 4.8% was also noted after three months of stable normoglycemia. UAE normalized in six of these subjects. A statistically significant correlation was also found between the changes in mean fasting plasma glucose and the decline in UAE (r=0.56 and p < 0.01). CONCLUSION: The study emphasizes the necessity to correct the apparently reversible increase in microabuminuria that accompanies hyperglycemia prior to patients recruitment for intervention therapy.

Albuminuria↗

Plasma concentrations of asymmetric-dimethyl-arginine in type 2 diabetes associate with glycemic control and glomerular filtration rate but not with risk factors of vasculopathy.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS). Increased plasma levels of ADMA may indicate endothelial dysfunction and increased risk of angiopathy. The relation of ADMA to diabetes, glycemic control, and renal function, especially early diabetic hyperfiltration, remains unknown. We tried to evaluate whether there is an association between ADMA and glycosylated hemoglobin (GHbA(1c)) on the one hand and glomerular filtration rate (GFR) on the other hand in diabetic subjects with normal or slightly increased GFR. We also studied whether plasma ADMA is associated with some risk factors of vasculopathy (hypercholesterolemia and hypertension). The study subjects consisted of 86 patients with type 2 diabetes and 65 control subjects. Plasma ADMA levels were measured by high-pressure liquid chromatography as o-pthalaldehyde (OPA) derivatives and GFR was determined by the plasma clearance of chromium 51-EDTA. The diabetic patients had lower plasma ADMA levels than the nondiabetic control subjects (0.29 +/- 0.15 v 0.34 +/- 0.16 micromol/L, P <.03). In the diabetic subjects, plasma ADMA concentrations were inversely correlated with GHbA(1c) (R = -0.28, P =.01). In a multivariate linear model, significant predictors of ADMA were GFR (R = -0.32, P =.008) in diabetic subjects and GHbA(1c) (R = -0.19, P =.03) and GFR (R = -0.19, P =.02) in all subjects. Plasma ADMA was not associated with risk factors of vasculopathy. We conclude that diabetic patients with a normal or slightly increased GFR have lower circulating ADMA concentrations than nondiabetic control subjects. In type 2 diabetic patients high GFR and poor glycemic control were related to low plasma ADMA concentrations.

Aged↗

Combined aerobic and resistance exercise improves glycemic control and fitness in type 2 diabetes.

We investigated the effect of an 8 week circuit training (CT) program, combining aerobic and resistance exercise, on indices of glycemic control, cardiorespiratory fitness, muscular strength and body composition in 16 subjects (age 52 +/- 2 years) with type 2 diabetes using a prospective randomised crossover protocol. Submaximal exercise heart rate and rate pressure product were significantly lower after training (P<0.05), whilst ventilatory threshold increased (11.8 +/- 0.7 vs 13.8 +/- 0.6 ml kg(-1)min(-1), P<0.001). Muscular strength also increased with training (403 +/- 30 to 456 +/- 31 kg, P<0.001), whilst skinfolds (148.7 +/- 11.5 vs 141.1 +/- 10.7 mm, P<0.05), % body fat (29.5 +/- 1.0 vs 28.7 +/- 1.1%, P<0.05) and waist:hip ratio (99.2 +/- 1.5 vs 97.9 +/- 1.4%, P<0.05) significantly decreased. Concurrently, peak oxygen uptake (P<0.05) and exercise test duration (P<0.001) increased following training, whilst glycated hemoglobin (P<0.05) and fasting blood glucose (P<0.05) decreased. CT is an effective method of training that improved functional capacity, lean body mass, strength and glycemic control in subjects with type 2 diabetes.

Blood Glucose↗

Hormone replacement therapy is associated with better glycemic control in women with type 2 diabetes: The Northern California Kaiser Permanente Diabetes Registry.

OBJECTIVE: In women with diabetes, the changes that accompany menopause may further diminish glycemic control. Little is known about how hormone replacement therapy (HRT) affects glucose metabolism in diabetes. The aim of this study was to examine whether HbA(1c) levels varied by current HRT among women with type 2 diabetes. RESEARCH DESIGN AND METHODS: In a cohort of 15,435 women with type 2 diabetes who were members of a health maintenance organization, HbA(1c) and HRT were assessed by reviewing records in the health plan's computerized laboratory and pharmacy systems. Sociodemographic and clinical information were collected by survey. RESULTS: The mean age was 64.7 years (SD +/- 8.7). The study cohort comprised 55% non-Hispanic whites, 14% non-Hispanic blacks, 12% Hispanics, 11% Asians, 4% "other" ethnic groups, and 4% with missing ethnicity data. Current HRT was observed in 25% of women. HbA(1c) levels were significantly lower in women currently using HRT than in women not using HRT (age-adjusted mean +/- SE: 7.9 +/- 0.03 vs. 8.5 +/- 0.02, respectively, P = 0.0001). No differences in HbA(1c) level were observed between women using unopposed estrogens and women using opposed estrogens. In a Generalized Estimating Equation model, which took into account patient clustering within physician and adjusted for age, ethnicity, education, obesity, hypoglycemic therapy, diabetes duration, self-monitoring of blood glucose, and exercise, HRT remained significantly and independently associated with decreased HbA(1c) levels (P = 0.0001). CONCLUSIONS: HRT was independently associated with decreased HbA(1c) level. Clinical trials will be necessary to understand whether HRT may improve glycemic control in women with diabetes.

Aged↗

Effect of computer-assisted insulin delivery on glycemic control of type I diabetic patients: a preliminary experience.

The aim of the study was to evaluate the effect of a computer-assisted insulin delivery on the glycemic control of type I unstable diabetic patients. 6 subjects, who already received 2-4 daily insulin injections, were treated with a pocket-size microprocessor device for periods lasting 2-14 months. The total daily insulin doses remained unchanged during the experimental period. However, the percentage of regular insulin decreased significantly from 63 +/- 3% to 47 +/- 7% (p less than 0.05). HbA1 levels decreased from 10.1 +/- 0.6% to 9.4 +/- 0.4% after 2 months computer (p less than 0.05). However, in the 2 patients who used the device for 11-14 months, the overall glycemic control was comparable during the basal and experimental periods. Hypoglycemic episodes were not increased.

Adult↗

Relationship between glycemic control and orthostatic hypotension in type 2 diabetes mellitus--a survey by the Fukuoka Diabetes Clinic Group.

We examined the prevalence of orthostatic hypotension and its association with glycemic control, as assessed by hemoglobin A1 (HbA1) concentration, in type 2 diabetic patients. The prevalence of orthostatic hypotension in 886 diabetics who were referred to our study and in 587 diabetics who were not given any antihypertensive drugs was 7% and 6%, respectively. The relationship between orthostatic hypotension and HbA1 levels was evaluated only in subjects not receiving antihypertensive drugs, since antihypertensive agents might induce orthostatic hypotension. HbA1 levels were 11.0 +/- 2.1% in the diabetic patients with orthostatic hypotension, which was significantly higher than the HbA1 levels of 9.9 +/- 2.2% in the diabetic patients without orthostatic hypotension. Multivariate analysis also revealed that the association remained significant after adjustment for the treatment and duration of diabetes, age, sex and body mass index. These findings suggest that glycemic control contributes to the development of orthostatic hypotension in type 2 diabetic patients.

Analysis of Variance↗

Glycemic control in patients with diabetes mellitus upon admission to a dental clinic: considerations for dental management.

OBJECTIVE: The purpose of this study was to determine the level of glycemic control in dental patients with diabetes upon admission to a dental school clinic. METHODS AND MATERIALS: One hundred patients (mean age: 57.7 years) of the Oral Diagnosis-Admissions Clinic at the University of Minnesota School of Dentistry, Minneapolis, Minnesota, with diabetes mellitus were chosen as subjects. Fasting blood glucose was measured using a portable blood glucose monitoring device as a part of their initial dental examination. RESULTS: Twenty-eight of the 100 patients were found to be hyperglycemic (> or = 126 mg/dl; 174.8 +/- 40.8 mg/dl; mean +/- SEM); 2 patients were found to be hypoglycemic (< 70 mg/dl). Of the 8 patients with type 1 diabetes in the cohort, 3 (37.5%) were very hyperglycemic, with fasting blood glucose levels > 250 mg/dl. CONCLUSIONS: This is important information for dental practitioners because patients with diabetes may not be under good glycemic control, and dentists may have to take special precautions before, during, and after treatment. This paper reviews the pathogenesis of diabetes, the detection of patients with undiagnosed or poorly controlled diabetes, and the management of patients with diabetes during dental treatment.

Blood Glucose↗

Strict glycemic control in diabetic dogs with closed-loop intraperitoneal insulin infusion algorithm designed for an artificial endocrine pancreas.

The ultimate goal of the development of an artificial endocrine pancreas is to achieve long-term strict glycemic regulation. To establish the physiological insulin delivery route of the artificial endocrine pancreas, intraperitoneal insulin infusion may be important. For this purpose, we tried to develop a closed-loop intraperitoneal insulin infusion algorithm by analyzing the pharmacokinetics of intraperitoneal regular insulin absorption using a mathematical model. The parameters for this algorithm were calculated to simulate the plasma insulin profile after intraperitoneal insulin injection as closely as possible. To evaluate the appropriateness of this algorithm, we tried glycemic control after an oral glucose load of 2 g/kg or a meal load of 80 kcal/kg in diabetic dogs by applying the algorithm. With the use of the subcutaneous insulin lispro infusion algorithm, which we have previously reported, alloxan-induced diabetic dogs exhibited postprandial hyperglycemia and delayed hyperinsulinemia, followed by hypoglycemia after an oral glucose load of 2 g/kg. However, by using the intraperitoneal insulin infusion algorithm, excellent glycemic control (postprandial blood glucose levels of 9.1 +/- 0.8 mmol/l at 70 min and 3.8 +/- 0.3 mmol/l at 240 min, respectively) could be achieved without any associated delayed hyperinsulinemia or hypoglycemia. Glycemic excursion after a meal load of 80 kcal/kg was also controlled from 3.9 to 10.1 mmol/l. Our results confirm that the intraperitoneal insulin infusion algorithm in vivo is feasible and that this algorithm can be superior to the subcutaneous insulin lispro infusion algorithm in the regulation of blood glucose.

Algorithms↗

Assessment of glycemic control after islet transplantation using the continuous glucose monitor in insulin-independent versus insulin-requiring type 1 diabetes subjects.

BACKGROUND: The aim of this study was to assess and compare glycemic control using the continuous glucose monitor (CGMS, Medtronic Minimed, Northridge, CA) in type 1 diabetes mellitus (T1DM) subjects who are insulin-independent versus those who require insulin after islet transplantation alone (ITA). METHODS: Glycemic control was assessed using 72-h CGMS in eight T1DM subjects who were insulin-independent after ITA (ITA-II), eight T1DM subjects who were C-peptide-positive but insulin-requiring after ITA (ITA-IR), and eight non-transplanted (NT) T1DM subjects. RESULTS: Standard deviation of glucose values was not significantly different between ITA-II and ITA-IR subjects (ITA-II, 1.2 +/- 0.1 mM; ITA-IR, 2.0 +/- 0.3 mM; P = 0.072). Both ITA groups were more stable than NT subjects (NT, 3.3 +/- 0.3 mM; P = 0.001 vs. ITA). Mean high glucose values were significantly lower in ITA subjects compared with NT subjects (ITA-II, 10.5 +/- 0.6 mM; ITA-IR, 13.0 +/- 1.0 mM; NT, 16.1 +/- 1.1 mM; P = 0.002). Mean average glucose values were not significantly different among all groups (ITA-I, 6.7 +/- 0.2 mM; ITA-IR, 7.8 +/- 0.3 mM; NT, 7.7 +/- 0.6 mM; P = 0.198). Mean low glucose values were significantly higher in both ITA groups compared with NT subjects (ITA-II, 4.5 +/- 0.2 mM; ITA-IR, 4.3 +/- 0.3 mM; NT, 3.0 +/- 0.2 mM; P = 0.003). Duration of hypoglycemic excursions (<3.0 mM) was markedly reduced in both ITA groups (ITA-II, 0%; ITA-IR, 2.4 +/- 0.2%; NT, 11.8 +/- 4.2%). Glycated hemoglobin was not significantly different between ITA groups (ITA-II, 6.4 +/- 0.2%; ITA-IR, 6.5 +/- 0.3%) and was significantly higher in NT subjects (8.3 +/- 0.2%; P < 0.001 vs. ITA). CONCLUSIONS: CGMS monitoring demonstrates that glycemic lability and hypoglycemia are significantly reduced in C-peptide-positive islet transplant recipients, whether or not supplementary, exogenous insulin is used, compared with non-transplanted T1DM subjects.

Adult↗

Impact of glycemic control on serum lipoprotein (a) in Arab children with type 1 diabetes.

BACKGROUND: Lipoprotein (a) (Lp (a)) is an independent risk factor for coronary artery disease (CAD), a major cause of death in patients with type 1 diabetes mellitus. Both type 1 diabetes and CAD represent major problems in Kuwait. Data on the effect of metabolic control on Lp (a) in diabetic children are limited and this is particularly true for Arab children. The objectives of the present study were to analyze serum Lp (a) levels in patients with type 1 diabetes compared with non-diabetic children, taking into account the effect of glycemic control. METHODS: Circulating lipids, including Lp (a), were measured in serum samples from 60 prepubertal non-diabetic children and 58 prepubertal children with type 1 diabetes. Comparisons of Lp (a) concentrations were made between the non-diabetic and diabetic children with good to fair control (glycosylated hemoglobin (GHb) <11%) and a group of diabetic children with poor control (GHb > or = 11%). RESULTS: The mean serum Lp (a) level in all diabetic children was 187.62+160.43 mg/L, compared with 162.88+156.06 mg/L in the control group. The group of children with poor glycemic control had higher median Lp (a) levels (147.50 mg/L) than either the group of diabetic children with good to fair control (95 mg/L; P<0.028) or the group of non-diabetic children (125 mg/L; P<0.04). Moreover, 38.3% of poorly controlled diabetic children had elevated Lp (a) levels > or = 250 mg/L, compared with 12.5% of diabetic children with good to fair control and 16.7% of non-diabetic children (P<0.025 and P<0.039, respectively). No association was found between Lp (a), diabetes duration and insulin dose. CONCLUSIONS: In Arab children, highest Lp (a) levels are associated with poorest metabolic control. The prevalence of Lp (a) levels associated with cardiovascular risk is higher in poorly controlled diabetic children. Increased levels of Lp (a) may be another contributing factor to the high risk for CAD in diabetic patients.

Arabs↗

Glycemic control during pancreas transplantation: continous infusion versus bolus.

Pancreas transplantation is a method to restore endogenous insulin secretion in insulin-dependent diabetic patients. Because glycemia >150 mg/dL may harm pancreatic graft beta cells, early glucose control using insulin administration is recommended during transplantation. The aim of this study was to evaluate the benefits of strict glycemic control during pancreas transplantation by comparing two types of insulin and glucose administration: continuous infusion and bolus. Capillary glucose was measured every 30 minutes after anesthetic induction for pancreas transplantation alone or simultaneously with kidney transplantation. Intravenous regular insulin was administered for values >150 mg/dL or glucose for values <100 mg/dL. The following timepoints were evaluated: anesthetic induction, before pancreatic graft reperfusion, and the first 4 minutes after reperfusion. Pancreatic graft ischemia time was significantly lower in the bolus group (P <.02). Immediately after reperfusion, there was a small increase in glycemia with a decrease in subsequent measurements in both groups. No significant difference in glycemia was observed between the groups at any time. Induction values were greater than all other timepoints in both groups. Glycemic control is important; it was successfully obtained with both methods. The trend to decrease glucose after reperfusion suggest early graft function.

Adult↗

A case of type 2 diabetes with a large abscess of the gastric wall successfully treated with a glycemic control and systemic antibiotics.

A case of type 2 diabetic patient, a 67-year-old woman, with a large abscess of the gastric wall which seemed to be a primary lesion is described for the first time. Fortunately, patient was successfully treated with both the maintenance of a good glycemic control and systemic antibiotics without laparotomy or drainage. Thus, a tight glycemic control and awareness of this disease should be reemphasized, and this may improve the prognosis of this rare and fatal one, even a poorly-controlled diabetes.

Abdominal Abscess↗

Diabetic nephropathy in adolescence: appearance during improved glycemic control.

Two girls, aged 15 and 14 years, with poorly controlled insulin-dependent diabetes (IDD) of 9 and 7 years duration, respectively, developed overt and persistent proteinuria shortly after rapid increases in insulin therapy and improved glycemic control. Renal biopsies showed diffuse diabetic glomerulosclerosis. Both patients maintained normal or increased creatinine clearances. Direct ophthalmoscopy and fluorescein retinal angiography demonstrated nonproliferative diabetic retinopathy in the first patient, which deteriorated after 6 weeks of strict metabolic control; the second patient had normal retinas. The appearance of clinical proteinuria during this brief period of good glycemic control suggests that the latter may have unmasked a preexisting condition. Possible pathophysiologic mechanisms initiating the proteinuria in these patients are reviewed.

Adolescent↗

Comparison of blood glucose profile and glycemic control in type 1 diabetic patients treated with Actrapid-Monotard or Actrapid Protaphane (NPH) human insulins.

The aim of this study is to compare the blood glucose profile and the glycemic control in Type 1 diabetic patients under two conventional semi-synthetic human insulin regimens (2 daily injections) combining regular (Actrapid) and intermediate acting insulins (Monotard or Protaphane). Actrapid-Monotard (scheme A) and Actrapid-Protaphane (scheme B) were administered during 3 months each, in a randomized order, to 18 outpatients. The glycemic control was evaluated by home glucose monitoring, as well as by the monthly measurements of HbA1. The total daily dose of insulin was comparable during each treatment period: 0.68 +/- 0.06 (scheme A) and 0.71 +/- 0.06 U/kg body wt. (scheme B) (mean +/- SEM). However, the total percentage of regular insulin was higher with Monotard than with Protaphane: 58 +/- 3 vs 48 +/- 5% in the morning (p less than 0.005) and 51 +/- 2 vs 46 +/- 3% in the evening (p less than 0.05). In C-peptide positive patients, the blood glucose values were comparable at all times with either insulin scheme. In contrast, in C-peptide negative patients, the blood glucose levels were higher in the afternoon with scheme B: 11.8 +/- 1 vs 8.6 +/- 1 mmol/l at 3 pm (p less than 0.02) and 12.2 +/- 1.3 vs 9.7 +/- 1.6 mmol/l at 6 pm (p less than 0.01). A slight but not significative increase of HbA1 was observed during the B period. In conclusion, an Actrapid-Protaphane scheme requires the use of a lower proportion of regular insulin than an Actrapid-Monotard treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗