Well-controlled Insulin-dependent Diabetes Mellitus Research Articles

54-Year-Old Man With Severe Prostatism, Palatal Mass, and History of Pancreatitis

54-year-old man with a history of benign prostatic hypertrophy, hypothyroidism, and well-controlled insulin-dependent diabetes mellitus secondary to idiopathic pancreatitis presented to our internal medicine consultation clinic. He complained of a lump in the hard palate, dry mouth present for 2 years, and bilateral submandibular gland swelling for which he had been evaluated by an otolaryngologist. A previous biopsy of the hard palate mass had demonstrated florid reactive lymphoid hyperplasia with fibrosis, polyclonal plasmacytosis and increased IgG4-positive plasma cells. He also complained of obstructive urinary symptoms and was found to have a very large and nodular prostate on digital rectal examination. The prostate-specific antigen level was 0.13 ng/mL (reference range, 0-3.2 ng/ mL), and results of urinalysis were unremarkable. A computed tomographic scan of the chest from an outside facility showed a mass in the right middle lobe in addition to bilateral renal lesions. Suspicion for a common link among his current symptoms and previous diagnoses was raised. 1. Which of the following is the most likely unifying diagnosis? a. Multiple myeloma b. Amyloidosis c. Metastatic prostate cancer d. IgG4-related sclerosing disease (IgG4RSD)

Fornix damage from solitary subependymal giant cell astrocytoma causing postoperative amnesic syndrome

The amnesic syndrome is characterized by difficulty learning and recalling information, either previously encoded (retro-grade) or newly encountered (anterograde). Various structures within the medial temporal lobe and limbic system of the brain are thought to be important in memory formation and retrieval, as evidenced by the fact that damage to these areas may result in an amnesic syndrome (Papanicolaou, 2006). For example, anterograde amnesia associated with damage to the fornix (Sweet et al, 1959), a fibre bundle connecting the hippocampus to the mamillary bodies within the limbic system, is well described following removal of third ventricle colloid cysts (Hodges and Carpenter, 1991; McMackin et al, 1995; Aggleton et al, 2000), suggesting the importance of the fornix as one of the anatomical substrates of the distributed neural network underpinning memory functions (Mesulam, 1990). This article reports the cognitive impairments associated with left fornix damage which became apparent following surgical removal of a solitary subependymal giant cell astrocytoma.

In vitro biological-to-immunological ratio of serum gonadotropins throughout male puberty in children with insulin-dependent diabetes mellitus

Information on the impact of prolonged deficient glycemic control in the quality of the gonadotropin signal delivered by the pituitary gland during puberty in children with insulin-dependent diabetes mellitus (IDDM) is scarce. In the present study, we examined the impact of deficient glycemic control on bioactive LH and FSH concentrations and their corresponding biological-to-immunological (B:I) ratio in boys with poorly controlled, but systemically uncomplicated IDDM. Dual control groups comprising patients with well-controlled IDDM and healthy boys of comparable age and body mass index were included for appropriate comparisons within and between each pubertal stage. Patients with poorly controlled and well-controlled IDDM exhibited serum bioactive FSH levels and B:I FSH ratio similar to those showed by the healthy control group. In contrast, in early and mid-pubertal boys with poorly controlled IDDM bioactive LH levels were normal, but its B:I LH relationship was significantly (P < 0.05) decreased. This attenuation in the quality of the LH signal did not affect total serum T concentrations, and apparently, progression of puberty. Long-standing uncontrolled diabetes and the consequent metabolic disturbances and/or complications may aggravate the reproductive axis dysfunction and eventually provoke pubertal arrest.

Increased levels of asymmetric dimethylarginine in populations at risk for atherosclerotic disease. Effects of pravastatin

The aim of the present study was to investigate plasma levels of asymmetric dimethylarginine (ADMA), an important endogenous inhibitor of nitric oxide synthase, in populations at high risk for atherosclerosis as compared to healthy controls, and furthermore to evaluate the effect of cholesterol lowering therapy in individuals with hypercholesterolemia. The present study consisted of 32 men with untreated hypercholesterolemia (HC group), 38 individuals with well-controlled insulin-dependent diabetes mellitus (DM group) and 20 healthy individuals (controls). The HC subjects were randomly allocated into a double blinded, placebo-controlled cross-over designed study with 8 weeks treatment with pravastatin (40 mg/day) or matching placebo. ADMA levels were statistically significantly higher in DM and HC individuals as compared to controls ( P<0.001 for both), and the l-arginine/ADMA ratios were significantly lower in both groups ( P<0.001 and P<0.005, respectively). Significant reductions in total cholesterol (TC) and LDL-C levels on pravastatin were obtained ( P<0.001 for both), whereas no changes were observed in the levels of ADMA or the l-arginine/ADMA ratios. Statistically significant correlations between ADMA and TC and LDL-C were found ( r=0.41, P<0.001 for both). In conclusion, significantly elevated ADMA levels and reduced l-arginine/ADMA ratios were found in individuals with diabetes type-1 as well as in hypercholesterolemia. Treatment with pravastatin 40 mg/day for 8 weeks had no effect on the levels of ADMA in hypercholesterolemic men.

Reactive oxygen species generation by leukocytes in populations at risk for atherosclerotic disease

The aim of this study was to investigate intracellular levels of reactive oxygen species (ROS) in circulating leukocytes in populations at risk for atherosclerosis compared with in healthy individuals. The study populations consisted of 27 non-diabetic men (aged 40 - 69 years) with untreated hypercholesterolemia (HC), 13 individuals (aged 39 - 56 years) with well-controlled insulin-dependent diabetes mellitus (DM), and 20 healthy individuals (aged 26 - 61 years) (REF). Citrated whole blood was collected in fasting condition. Using flow cytometric techniques, the resting levels and the response upon phorbol 12-myristate 13-acetate (PMA, 100 ng/mL) stimulation of ROS were measured in circulating monocytes (MO) and granulocytes (GR). The relative mean fluorescence intensity (rMFI) in 10 4 leukocytes of fluorochromes mainly reflecting the levels of peroxynitrite (ONOO - ) hydrogen peroxide (H 2 O 2 ) and superoxide anion (O 2 - ) was recorded. Significantly, higher basal levels of ONOO - in GR from the combined risk population compared with REF were found (1.4 vs. 1.5 rMFI, p<0.05). Upon PMA stimulation, significantly lower levels of O 2 - in GR in the risk populations compared to REF (119 vs. 90 Si, p<0.001) were observed. In conclusion, increased resting levels of ROS in circulating granulocytes, but reduced response to PMA stimulation could be demonstrated in populations at risk for atherosclerosis compared with in healthy individuals. This might indicate a higher degree of resting oxidative reactions, with partly exhausted cells and less capacity to host defence.

Profound changes in the GH-IGF-I system in adolescent girls with IDDM: can IGFBP1 be used to reflect overall glucose regulation?

Disturbances in the relations between insulin, growth hormone (GH) and insulin-like growth factor I (IGF-I) may be a major cause behind deteriorated metabolic control in adolescent girls with type I diabetes. These patients have increased GH secretion and low IGF-I concentrations. The aim of this study was to identify possible endocrine mechanisms behind good and poor glycaemic control in such girls, focusing on the insulin-GH-IGF-I axis. Ten girls with well-controlled insulin-dependent diabetes mellitus (IDDM), hemoglobin A1c (HbA1c) 6.5+/-0.4% (normal range 3.9-5.2%) and nine healthy controls were investigated and compared with 11 girls with poor glucose regulation, HbA1c 10.9+/-0.4%, and their corresponding controls. Serum profiles of glucose, insulin, GH and IGF-binding protein 1 (IGFBP1) were analysed in addition to IGF-I and HbA1c. Two interesting observations were made. GH concentrations were equally elevated in the two diabetic groups regardless of metabolic control (mean 24 h GH - girls with poorly controlled diabetes 10.0+/-1.0 mU/L vs 9.8+/-1.7 - girls with well-controlled diabetes; p=ns). Likewise, the IGF-I concentrations were reduced to the same extent (233+/-19 vs 242+/-23 microg/L; p=0.75). Secondly, despite similar insulin concentrations (mean 24 h insulin - girls with poorly controlled diabetes 22.9+/-2.6 and girls with well-controlled diabetes 27.3+/-2.9 mU/L, respectively; p=0.26), there was a marked difference in IGFBP1 concentrations between the two groups with IDDM (mean IGFBP1 - girls with poorly controlled diabetes 70.5+/-9.1 microg/L vs girls with well-controlled diabetes 28.6+/-3.3; p<0.001). Despite equally elevated GH concentrations that may induce insulin resistance, the markedly lower concentrations of IGFBP1 in the well-controlled group indicate a higher hepatic insulin sensitivity in these girls compared with those with a poor control. Furthermore, in spite of similar total IGF-I concentrations, the lower IGFBP1 concentrations may result in higher IGF-I bioactivity in the well-controlled group. This may be reflected in better growth of the well-controlled group whose height of 168.7+/-0.9 vs 163.6+/-1.2 cm was significantly different (p<0.004). IGFBP1 may be a marker of overall insulinization in adolescents with type 1 diabetes, independent of the absolute insulin dose used for therapy.

Aerobic circuit exercise training: Effect on adolescents with well-controlled insulin-dependent diabetes mellitus

Objectives: To test the safety and effects of exercise conditioning on cardiorespiratory fitness, body composition, muscle strength, glucose regulation, and lipid/cholesterol levels. Subjects: Ten male adolescents with insulin-dependent diabetes mellitus (IDDM) and 10 adolescent nondiabetic (ND) subjects. Design: Pretest, posttest intervention trial with control group. Setting: University-based human performance laboratory. Intervention: Mixed endurance and calisthenic/strength activities performed at a rapid pace three times weekly for 12 weeks. Results: Only one subject with IDDM experienced hypoglycemia after a single exercise session. Both subject groups improved their cardiorespiratory endurance ( p < .05). Lean body mass of IDDM subjects increased by 3.5% ( p < .05). Subjects with and without IDDM lowered their percent body fat ( p < .05 and .001, respectively). Strength improvement of IDDM subjects ranged from 13.7% ( p < .001) to 44.4% ( p < .01), depending upon the maneuver. Fasting blood plasma glucose for all subjects was unchanged by training, but glycosylated hemoglobin A 1c of IDDM subjects was reduced by .96 percentage point ( p < .05). Reductions of HbA 1c benefitted subjects exhibiting poor preconditioning glycemic control. Low-density lipoprotein cholesterol was decreased in subjects with IDDM ( p < .05), but not total cholesterol or triglycerides. Conclusion: Adolescents with IDDM undergoing aerobic circuit training improve their cardiorespiratory endurance, muscle strength, lipid profile, and glucose regulation. Aerobic circuit training is safe for properly trained and monitored adolescent diabetics.

BLOOD GLUCOSE RESPONSE TO RECREATIONAL DIVING IN INSULIN-DEPENDENT DIABETICS

1109 Insulin-dependent diabetes mellitus (IDDM) has traditionally excluded people from participation in scuba diving. However, a growing record of safe diving in defiance of this ban is prompting reassessment. The purpose of this study was to measure blood glucose in divers with IDDM during the course of a multi-day diving vacation. Sixteen certified divers (nine male: 43±8 y[mean±SD], 85.1±14.1 kg, 1.77±0.12 m, 27.4±5.3 kg·m-2; and seven female: 44±5 y, 66.6±14.2 kg, 1.62±0.07 m, 25.3±5.3 kg·m-2) with a history of well-controlled IDDM (confirmed by HbA lc test no higher than 9% and physician documentation) participated in one of two, week-long subtropical diving trips. Participants could dive up to four times per day, with blood glucose measured using a calibrated glucometer at 60, 30 and 5-10 min pre-dive, and immediately post-dive. Divers were restricted from diving if blood glucose level was below 80 mg·dL-1 immediately preceding a dive. A total of 131 dives were monitored. Divers conducted 8.2±3.3 dives per trip, 2.0±0.5 dives per day, with mean underwater time and depth of 38±7 min and 60±16 feet seawater, respectively. TableTablePost-dive blood glucose was <100 mg·dL-1 following 13 dives, <80 following four and <65 following one dive (47 mg·dL-1). Divers refrained from making a dive in five instances because of inability to eat due to seasickness. There were no complications related to low blood glucose levels arising from any dives. These findings are consistent with recent observations that individuals with well-controlled IDDM may safely participate in recreational scuba diving under moderate conditions.

Prolactin and β-endorphin responses to hypoglycemia are reduced in well-controlled insulin-dependent diabetes mellitus

Several pituitary hormones, including corticotropin (ACTH), growth hormone (GH), prolactin, and β-endorphin (but not thyrotropin, follicle-stimulating hormone, or luteinizing hormone), are released in response to hypoglycemia in normal subjects. In patients with insulin-dependent diabetes mellitus (IDDM), the degree of glycemic control is known to alter ACTH and GH responses to hypoglycemia. The current study was performed to examine the effect of glycemic control on prolactin and β-endorphin responses to hypoglycemia in subjects with IDDM. We performed 3-hour stepped hypoglycemic-hyperinsulinemic clamp studies (12 pmol/kg/min) during which plasma glucose was decreased from 5.0 mmol/L to 2.2 mmol/L in steps of 0.6 mmol/L every 30 minutes in 20 subjects with uncomplicated IDDM (12 males and eight females; age, 26 ± 2 years; IDDM duration, 10 ± 1 years; body mass index, 23.6 ± 0.6 kg/m 2) and 10 healthy subjects (five males and five females aged 30 ± 1 years). The 10 diabetic subjects in good glycemic control (mean hemoglobin A 1 [HbA 1], 7.5% ± 0.3%; normal range, 5.4% to 7.4%) were compared with the 10 poorly controlled patients (mean HbA 1, 12.6% ± 0.5%; P < 0.001 v well-controlled diabetic group). During hypoglycemia, prolactin levels in the well-controlled diabetic group did not change (7 ± 1 μg/L at plasma glucose 5.0 mmol/L to 9 ± 2 μg/L at plasma glucose 2.2 mmol/L), whereas prolactin levels increased markedly in the poorly controlled diabetic group (7 ± 2 μg/L to 44 ± 17 μg/L) and healthy volunteers (12 ± 2 μg/L to 60 ± 19 μg/L, P < .05 between IDDM groups). The plasma glucose threshold required for stimulation of prolactin secretion was 2.2 ± 0.1 mmol/L in well-controlled IDDM, 3.0 ± 0.4 mmol/L in poorly controlled IDDM, and 2.4 ± 0.1 mmol/L in healthy subjects ( P < .05 between IDDM groups). Responses in males and females were similar. The increase in β-endorphin levels was also attenuated in well-controlled IDDM patients (4 ± 1 pmol/L at plasma glucose 5.0 mmol/L to 11 ± 4 pmol/L at plasma glucose 2.2 mmol/L) versus poorly controlled IDDM patients (5 ± 1 pmol/L to 26 ± 7 pmol/L) and healthy subjects (8 ± 1 pmol/L to 56 ± 13 pmol/L). The plasma glucose threshold required for stimulation of β-endorphin release was again lower in well-controlled IDDM versus poorly controlled IDDM patients (2.2 ± 0.1 v 3.0 ± 0.3 mmol/L) and healthy subjects (2.5 ± 0.4 mmol/L, P < .05 between IDDM groups). In conclusion, prolactin and β-endorphin responses to a standardized hypoglycemic stimulus (plasma glucose, 2.2 mmol/L) are reduced and plasma glucose levels required to stimulate release of prolactin and β-endorphin are lower in well-controlled IDDM compared with poorly controlled IDDM and healthy subjects. Thus, stress hormones not previously considered to have a primary role in plasma glucose recovery from hypoglycemia are affected by glycemic control, suggesting a more generalized alteration of hypothalamic-pituitary responses to hypoglycemia in IDDM patients with strict glycemic control.

Cardiac Doppler Flow Velocities in Fetuses of Well- Controlled Insulin-Dependent Diabetic Mothers

The advent of Doppler echocardiography has permitted noninvasive examination of the fetal heart. In this study, computer-assisted cardiac Doppler flow velocity waveform (DFVW) analysis was used to determine whether diastolic dysfunction is manifest in the fetuses of diabetic mothers. Diastolic atrioventricular (AV) valve flow was measured in the fetuses of 40 women with well-controlled insulin-dependent diabetes mellitus (IDDM) at 18 to 22 weeks (timepoint A) and 30 to 35 weeks (timepoint B) gestation. These subjects were compared to 40 age-matched pregnant non-diabetic controls, and their maternal glycosylated hemoglobin HbA1c fractions (%) were measured to gauge the adequacy of glycemic control. HbA1c fractions showed no statistically significant difference between timepoints A and B (4.85 ± 0.2% and 5.16 ± 0.3%, respectively), and demonstrated a well-controlled diabetic state.At timepoint A, the peak velocity of rapid ventricular filling [E (cm/s)] through both AV valves, the peak velocity of atrial contraction [A (cm/s)] through the tricuspid valve, and the flow integral measurement for atrial contraction [AI (cm)] through the tricuspid valve were significantly (p &lt; 0.05) higher than those measured in the controls. Peak velocities of atrial contraction and rapid ventricular filling (A and E, respectively) for both valves, as well as the flow integral of rapid ventricular filling (EI) for the tricuspid valve, were significantly (p &lt; 0.05) higher in fetuses of diabetic mothers at timepoint B than in controls. Overall, despite the fact that both IDDM and non-diabetic mothers showed significant (p &lt; 0.05) fetal increases in rapid ventricular filling (E) between the two timepoints, the ratios E/A and EI/AI for both valves were not modified in the two study groups at either gestational age. These results therefore substantiate rare previous findings that only peak velocity of rapid ventricular filling (E) is increased, despite expected changes in E/A and EI/AI ratios, with gestational age. Furthermore, the results of the present study suggest that fetal diastolic function is not adversely affected in well-controlled maternal IDDM.

Contraception guidance in women with pre-existing disturbances in carbohydrate metabolism

To review our studies on the clinical and metabolic impact of contraceptive methods in women with insulin dependent diabetes mellitus (IDDM) and women with previous gestational diabetes mellitus (GDM) in order to provide suggestions for the contraceptive counselling of these women. The clinical events following first insertions of copper IUDs were studied in 103 women with IDDM and in 119 non-diabetic women. Moreover we studied the effects on glycometabolic control and lipid metabolism in women with well-controlled IDDM using low-dose oral contraceptives (OCs) containing ethinylestradiol combined with norethisterone (n = 10), levonorgestrel (n = 9) or gestodene (n = 11). Hemostatic and endothelial function was also studied in the women using the gestodene-containing preparation. Finally, we studied the impact of oral contraceptives on the insulin sensitivity in women with previous GDM. The continuation rates and indications for medical removal of the IUDs were similar in the diabetic and the non-diabetic women. There was no increased pregnancy rate or increased frequency of pelvic inflammatory disease in the diabetic women. The glycemic control was not changed by the OCs and none of the treatment regimens were associated with changes in plasma lipids linked to increased risk of atherosclerosis. Indications of increased fibrin formation, which seemed to be compensated by increased fibrinolytic activity, were noted with the gestodene-containing preparation. None of the women developed microalbuminuria during the study. Compared to normal women, we found reduced insulin sensitivity in the women with previous GDM using the pill. Intrauterine devices and barrier methods can be used by diabetic women with the same reservations as in the general population. Low-dose OCs do not influence the glycemic control and have no adverse impact on plasma lipids. The balance between fibrin formation and resolution was maintained during intake of the gestodene-containing pill. Our findings suggest that combined oral contraceptives can be used in women with uncomplicated IDDM and in women with previous GDM if clinical and metabolic monitoring can be ensured.

Hormonal Contraception in Women With IDDM: Influence on glycometabolic control and lipoprotein metabolism

Safe and effective contraceptive methods are essential for women with insulin-dependent diabetes mellitus (IDDM), but opinions on the use of hormonal oral contraceptives by these women are conflicting. We evaluated the effects on glycometabolic control and lipoprotein metabolism in women with IDDM treated with an oral contraceptive not previously studied in a diabetic population. A total of 22 women with IDDM received a monophasic combination of ethinyl estradiol and gestodene for 1 year; 20 women of comparable diabetic status using nonhormonal contraception were selected as control subjects. Evaluation was performed before and after 1, 3, 6, and 12 months of hormonal intake using nonparametric statistical methods. Except for a higher median age of the control group, the baseline values for all clinical and metabolic variables were similar in the two groups, and in neither of the groups were changes in blood pressure, body mass index, or glycemic control observed. In the oral contraceptive group, decreased serum levels of low-density lipoprotein (LDL) cholesterol and increased levels of triglycerides and lipoprotein A were noted, whereas total cholesterol and high-density lipoprotein cholesterol levels were unchanged. In the control group, a decrease of LDL cholesterol was observed. No effect of tobacco smoking on glycometabolic control or lipoprotein metabolism could be demonstrated during hormonal intake. No evidence of impaired glycometabolic control or adverse changes in serum levels of lipoproteins known to be associated with atherosclerosis was observed in women with well-controlled IDDM during 1 year of oral contraception with ethinyl estradiol and gestodene.

Intraperitoneal insulin therapy corrects abnormalities in cholesteryl ester transfer and lipoprotein lipase activities in insulin-dependent diabetes mellitus.

Patients with insulin-dependent diabetes mellitus (IDDM) have proatherogenic disturbances in cholesteryl ester transfer (CET) despite intensive subcutaneous insulin therapy (ISC). Since CET is activated by insulin-sensitive lipoprotein lipase (LPL), which normally increases postprandially, we queried whether iatrogenic hyperinsulinism from ISC stimulated LPL and CET by studying well-controlled IDDM patients after ISC and then 6 months after lowering systemic insulin levels by intraperitoneal (IP) insulin delivery. Although glycemic control (HbA1c IDDM, 6.9 +/- 1.7%; control, 4.5% to 8%) was excellent during ISC, CET was accelerated (P < .001) and both systemic insulin levels and LPL specific activity were increased (P < .05). Following IP, basal systemic insulin levels declined by more than one half (ISC, 8.22 +/- 6.5 versus IP, 2.77 +/- 2.4 microU/mL; mean +/- SD; P < .025), and both LPL and CET activities returned to normal. Plasma triglyceride, cholesterol, high-density lipoprotein-2 (HDL2) cholesterol, HDL3 cholesterol, cholesteryl ester transfer protein mass, and glycemic control (HbA1c, 6.3 +/- 0.8%) were unchanged and remained normal. These findings indicate that ISC is associated with high levels of basal CET and LPL. These alterations both appear to be closely linked to iatrogenic hyperinsulinemia resulting from ISC. The fact that they are both reversed when systemic insulin levels are reduced by IP suggests that insulin, acting through LPL, influences the nature of the interaction of the lipoproteins engaged in CET.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased serum angiotensin converting enzyme activity in type I insulin-dependent diabetes mellitus: its relation to metabolic control and diabetic complications.

Serum angiotensin-converting enzyme (ACE) was measured in 150 insulin-dependent diabetes mellitus (IDDM) patients and 72 healthy subjects by radioassay, using [3H]-hippuryl-glycyl-glycine as a substrate. Mean (SD) serum ACE activity in diabetic patients was 120 +/- 33 nmol ml-1 min-1 (range 46-215) and was significantly increased by 56% compared to control values (77 +/- 23 nmol ml-1 min-1, range 46-125, P < 0.001). ACE activity > 125 nmol ml-1 min-1 was observed in 60 of 150 IDDM patients. 96 IDDM patients were normoalbuminuric (< 22 mg 24 h-1) and 49 patients were micro- or macroalbuminuric (range 22-6010 mg 24 h-1). Micro- and macroalbuminuric IDDM patients were found to have significantly greater ACE activity values than normoalbuminuric patients (128 +/- 36 vs. 115 +/- 30 nmol ml-1 min-1, P = 0.025). Metabolically well-controlled IDDM patients (glycosylated haemoglobin < or = 8%) had lower ACE activity values than the patients with glycosylated haemoglobin greater than 8% (109 +/- 20 vs. 127 +/- 32 nmol ml-1 min-1, P < 0.02). A significant correlation between degree of metabolic control and ACE activity was found (r = 0.435, P < 0.001) so that an increase in one glycosylated quartile unit is accompanied by an increase in ACE activity of 10.5 nmol ml-1 min-1. Thus ACE activity in the serum of IDDM patients was increased by 56% in 40% of the patients. It was increased in IDDM patients without complications and in patients with retinopathy or nephropathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities in the renal and vascular responses to LBNP in humans with early diabetes.

Plasma atrial natriuretic factor (ANF) concentrations are increased in subjects with insulin-dependent diabetes mellitus (IDDM). A potential contribution of ANF to the maintenance of abnormalities in renal hemodynamic function has been considered but not proven in human diabetic subjects. The aim of these experiments was to determine the response of renal blood flow (RBF), glomerular filtration rate (GFR), filtration fraction (FF), and urinary sodium excretion (UNaV) to a reduction of plasma ANF concentrations induced by application of nonhypotensive lower body negative pressure (LBNP) in a group of subjects with early, uncomplicated, well-controlled IDDM compared with control subjects. Baseline supine measurements before LBNP revealed the diabetic subjects to have a significantly higher plasma ANF (31 +/- 2 vs. 24 +/- 2 pg/ml, P = 0.05). GFR tended to be higher (118 +/- 11 vs. 104 +/- 9 ml/min) and UNaV tended to be depressed (188 +/- 25 vs. 240 +/- 25 mumol/min) despite equal sodium intake, but not significantly so. In addition IDDM subjects exhibited significantly lower baseline plasma norepinephrine (PNE) concentrations (0.91 +/- 0.20 vs. 1.60 +/- 0.2 nmol/l, P = 0.03). Forearm vascular resistance (FVR) was not significantly different between the two groups (29 +/- 5 vs. 33 +/- 5 units). LBNP induced comparable decreases in ANF and central venous pressure (CVP) in both groups. The anticipated renal response to ANF reduction (declines in GFR, FF, and UNaV) occurred only in the normal control group. The percent decline in GFR (11% vs. 34.5%, P = 0.01) was markedly attenuated in IDDM subjects. The expected reflexive increase in PNE and FVR also did not occur in IDDM subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of prolonged hyperglycemia on growth hormone levels and insulin sensitivity in insulin-dependent diabetes mellitus

The aim of the present study was to characterize the effect of a hyperglycemic period (44 hours) on the levels of insulin-antagonistic hormones and insulin sensitivity in seven subjects with well-controlled insulin-dependent diabetes mellitus (IDDM). Hyperglycemia (∼15 mmol · L −1) was induced by a glucose infusion while the degree of insulinization was similar to that of the period with near normoglycemia (∼6.9 mmol · L −1). Insulin sensitivity was measured with hyperinsulinemic euglycemic clamps performed 4 hours before and after the periods of normoglycemia (control) and hyperglycemia. d-[3- 3H]glucose was infused in the second clamp in each study to evaluate glucose production and utilization. Since growth hormone (GH) levels frequently are elevated during poor diabetic control, diurnal GH secretion was measured in blood samples continuously drawn for 24 hours during the euglycemic and hyperglycemic periods. Levels of epinephrine, norepinephrine, cortisol, and nonesterified free fatty acids (NEFA) were similar during the control and hyperglycemic periods and during the clamps. GH levels were also similar, but an abnormal diurnal secretion pattern was present with increased numbers of daytime peaks. Hyperglycemia did not reduce GH secretion in IDDM. Hyperglycemia for 44 hours induced insulin resistance (32% reduction of glucose infusion rate, P < .02). In the control study, a 21% reduction ( P = .064, NS) of the glucose disposal rate (R d) was seen, suggesting that the hospitalization period per se may also reduce insulin sensitivity. In conclusion, a period of hyperglycemia leads to insulin resistance in IDDM patients. This insulin resistance cannot be attributable to increased levels of insulin-antagonistic hormones, although an abnormal secretion pattern for GH was found. Thus, hyperglycemia per se seems to be an important reason for the insulin resistance in IDDM.

Renal Function and Renal Function Reserve in Insulin-Dependent Diabetic Patients during (Near) Normoglycaemia

Twenty-three normoalbuminuric (N) and 7 microalbuminuric (M) insulin-dependent diabetes mellitus (IDDM) patients were studied under (near) normoglycaemic conditions. They were reasonably well controlled during the period preceding the renal function test (HbA1: N = 7.6 +/- 1.3%, N = 8.0 +/- 2.2%; normal less than 6.0%). Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured using the clearances of 125I-thalamate and 131I-hippuran, respectively. The renal reserve filtration capacity (RRFC) was tested by using a combination of a liquid mixed meal and an amino acid infusion. Blood glucose levels were kept as constant as possible throughout the testing procedure, both under baseline (BL) conditions and after stimulation (S). Under such (near) normoglycaemic conditions, no BL GFR values exceeding 150 ml/min/1.73 m2 could be established. Furthermore, a RRFC could be established in all patients. Both groups showed a comparatively larger increase in GFR (N 13.0 +/- 3.8%, M 10.8 +/- 3.6%) than in ERPF (N 4.8 +/- 7.0%, M 2.2 +/- 5.8%; % delta GFR vs. % delta ERPF p less than 0.01), resulting in a higher filtration fraction (FF) during stimulation (N: BL FF 0.25 +/- 0.03 vs. S FF 0.27 +/- 0.03, p less than 0.01; M: BL FF 0.25 +/- 0.01 vs. S FF 0.27 +/- 0.01, p less than 0.05). This suggests afferent vasodilation during stimulation in these (near) normoglycaemic, reasonably well-controlled IDDM patients, a situation comparable to that in non-diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral blood flow and substrate utilization in insulin-treated diabetic subjects

We compared regional cerebral blood flow (rCBF) and arteriojugular vein differences of glucose, ketones, glycerol, lactate, pyruvate, and O2 in eight subjects with well-controlled insulin-dependent diabetes mellitus (IDDM) and in six healthy volunteers. Duration of diabetes was 19.4 +/- 2.1 yr. Measurements were performed before and after 120 min of insulin infusion and concomitant Biostator-controlled normoglycemia. Net uptake of ketones was seen in IDDM subjects before but not after insulin. Net uptake of glucose did not differ significantly between groups. During normoglycemia the molar ratio of O2 to glucose uptake was lower in IDDM than in nondiabetic subjects (4.68 vs. 5.50; P less than 0.05; Wilcoxon test). Small but significant release of lactate and pyruvate was seen in IDDM but not in nondiabetic subjects. The rCBF was measured by 11CH3F and position emission tomography. Global mean CBF was higher in IDDM subjects (64.9 +/- 5.9 vs. 49.3 +/- 2.7 ml.100 g-1.min-1, means +/- SE in nondiabetic subjects, P less than 0.05). rCBF was enhanced in many cortical and subcortical areas, whereas it was decreased in the head of the caudate nucleus. Neuropsychological testing did not reveal obvious cognitive dysfunction. The results imply that a larger fraction of glucose is nonoxidatively metabolized in the IDDM subjects and furthermore indicate an abnormal rCBF pattern in these subjects.

D-[U-11C]glucose uptake and metabolism in the brain of insulin-dependent diabetic subjects

We used D-[U-11C]glucose to evaluate transport and metabolism of glucose in the brain in eight nondiabetic and six insulin-dependent diabetes mellitus (IDDM) subjects. IDDM subjects were treated by continuous subcutaneous insulin infusion. Blood glucose was regulated by a Biostator-controlled glucose infusion during a constant insulin infusion. D-[U-11C]-glucose was injected for positron emission tomography studies during normoglycemia as well as during moderate hypoglycemia [arterial plasma glucose 2.74 +/- 0.14 in nondiabetic and 2.80 +/- 0.26 mmol/l (means +/- SE) in IDDM subjects]. Levels of free insulin were constant and similar in both groups. The tracer data were analyzed using a three-compartment model with a fixed correction for 11CO2 egression. During normoglycemia the influx rate constant (k1) and blood-brain glucose flux did not differ between the two groups. During hypoglycemia k1 increased significantly and similarly in both groups (from 0.061 +/- 0.007 to 0.090 +/- 0.006 in nondiabetic and from 0.061 +/- 0.006 to 0.093 +/- 0.013 ml.g-1.min-1 in IDDM subjects). During normoglycemia the tracer-calculated metabolism of glucose was higher in the whole brain in the nondiabetic than in the diabetic subjects (22.0 +/- 1.9 vs. 15.6 +/- 1.1 mumol.100 g-1.min-1, P less than 0.01). During hypoglycemia tracer-calculated metabolism was decreased by 40% in nondiabetic subjects and by 28% in diabetic subjects. The results indicate that uptake of glucose is normal, but some aspect of glucose metabolism is abnormal in a group of well-controlled IDDM subjects.

Leucine Metabolism in IDDM: Role of Insulin and Substrate Availability

The effect of insulin on plasma amino acid concentrations and leucine metabolism was examined in 18 healthy nondiabetic young volunteers and in 7 subjects with insulin-dependent diabetes mellitus (IDDM) with the euglycemic insulin-clamp technique (40 mU.m-2.min-1) in combination with [1-14C]leucine. All diabetic subjects were studied while in poor metabolic control (fasting glucose 13.3 +/- 1.1 mM; HbA1c 10.8 +/- 0.2%) and again after 2 mo of intensified insulin therapy (fasting glucose 7.2 +/- 0.5 mM; HbA1c 8.0 +/- 0.2%). Insulin-mediated total-body glucose uptake in poorly controlled diabetic subjects (3.6 +/- 0.5 mg.kg-1.min-1) was significantly reduced compared with control subjects (7.5 +/- 0.2 mg.kg-1.min-1; P less than .001) and improved slightly after insulin therapy (4.8 +/- 0.3 mg.kg-1.min-1; P less than .05), although it still remained significantly lower than in control subjects (P less than .01). During the insulin-clamp study performed in subjects with poorly controlled IDDM, endogenous leucine flux (ELF), leucine oxidation (LO), and nonoxidative leucine disposal (NOLD) all decreased (50.1 +/- 2.0 to 26.4 +/- 0.4; 9.2 +/- 0.4 to 6.0 +/- 0.3; 40.9 +/- 2.0 to 20.4 +/- 2.0 mumol.m-2.min-1, respectively) to the same extent as in control subjects. After 2 mo of intensified insulin therapy, the effect of acute hyperinsulinemia on ELF, LO, and NOLD was comparable to that of control subjects, whereas insulin-stimulated glucose metabolism was still impaired. To examine the effect of substrate availability on leucine turnover, well-regulated IDDM and control subjects underwent a repeat insulin-clamp study combined with a balanced amino acid infusion designed to increase circulating plasma amino acid levels approximately twofold. Under these conditions, NOLD was equally enhanced above baseline in both control and IDDM subjects (P less than .01), whereas ELF was inhibited to a greater extent (P less than .01) than during the insulin clamp performed without amino acid infusion (control vs. diabetic subjects, NS). In conclusion, insulin-mediated glucose metabolism is severely impaired in subjects with both poorly controlled and well-controlled IDDM, whereas the effect of acute insulin infusion on leucine turnover is normal, and combined hyperaminoacidemia/hyperinsulinemia stimulated NOLD to a similar extent in both IDDM and control subjects.