Severe hypoglycemia in diabetic patients: frequency, causes, prevention.

Over a 12-mo period, the frequency of severe hypoglycemic episodes was measured in a population of approximately 400 (50% type I) diabetic patients treated with insulin. There were 32 severe insulin reactions in 26 patients, a patient-yr incidence of 8%. The major precipitating causes were patients' errors (nine), and too much insulin or a wrong combination (six). In seven cases no cause could be found. For the group as a whole there was clear evidence of overtreatment as measured by insulin doses (0.89 +/- 0.43 U/kg/day versus 0.65 +/- 0.34 U/kg/day in a convenience group of 100 patients from the same diabetic population [P less than 0.05] ). Furthermore, 6-12 mo after the event the mean insulin dose had decreased from 0.82 +/- 0.25 to 0.69 +/- 0.27 U/kg/day in the subgroup of 20 hypoglycemic patients that could be followed (P less than 0.001). The mean HbAlc levels of the hypoglycemic group and the control group differed significantly (8.1 +/- 1.3% versus 8.7 +/- 1.7%, P less than 0.05). Six to 12 mo after the reaction, the mean HbAlc level in the follow-up subgroup rose from 8.1 +/- 1.3% to 9.1 +/- 1.1% (P less than 0.05). Patients' errors as a cause of the insulin reaction were not only the result of the patients' deficient knowledge but more often of lack of alertness and carelessness. We conclude that it is not possible to prevent all the severe hypoglycemic reactions in diabetic patients. However, besides avoiding overtreatment by the physician, teaching patients to respond more adequately to changing circumstances in daily life or to warning signs could also reduce the incidence of hypoglycemia.

Prevalence of "syndrome X" features in parents of type 1 diabetic patients with or without nephropathy.

OBJECTIVE: To compare the prevalence of "syndrome X"-related parameters in parents of type 1 diabetic patients with diabetic nephropathy (DNP) to those in parents of diabetic patients without DNP. RESEARCH DESIGN AND METHODS: In this cross-sectional study, we included 50 parents of type 1 diabetic patients with DNP and 50 parents of diabetic patients without DNP. All parents were investigated in a fasting state for serum lipids including nonesterified fatty acids (NEFAs), glucose, HbA1c, plasma uric acid, fasting insulin levels, and albuminuria. Blood pressure was recorded in the supine position using an automatic device; ankle/brachial index was measured with Doppler ultrasound. Presence of cardiovascular disease was determined by a standardized questionnaire and electrocardiogram registration. Subjects without known diabetes underwent a 2-h oral glucose tolerance test. Anthropometric parameters such as BMI, waist-to-hip ratio, and percentage of body fat were measured. In addition to univariate analysis, a syndrome X score (SXS) was formulated, comprising a number of syndrome X-related biochemical, physiological, and/or anthropometric parameters. RESULTS: Univariate analysis revealed no significant differences in syndrome X parameters between parents of type 1 diabetic patients with or without DNP. Also, the composite SXS was similar in both groups. CONCLUSIONS: In this study, no differences were found in the prevalence of syndrome X features between parents of type 1 diabetic patients with DNP and parents of patients without DNP.

A comparison of the hypotensive effects of captopril and atenolol in the treatment of hypertension in diabetic patients.

In a double-blind, randomized, cross-over study in 23 diabetic patients, insulin treated (N = 11) or noninsulin treated (N = 12), with mild to moderate hypertension, the hypotensive effects of captopril and atenolol were compared. Five patients had overt diabetic nephropathy. All patients received 50 mg twice daily of either drug. Treatment periods lasted 6 weeks and were preceded and separated by a placebo period. Two patients dropped out, one because of intermittent claudication during atenolol, one with cardiac arrhythmia during placebo. Blood pressure was reduced from 165 +/- 5/96 +/- 1 to 154 +/- 5/89 +/- 2 mmHg (mean +/- SEM: P less than 0.01) during captopril and from 171 +/- 5/98 +/- 1 to 159 +/- 6/89 +/- 2 mmHg (P less than 0.01) during atenolol. These antihypertensive effects are not significantly different. There was a wide inter- and intraindividual variation in hypotensive response to both drugs, which may have important consequences for treatment strategies. No consistent differences between insulin and noninsulin treated patients were seen. Parameters of glycemic control did not change during any therapy, neither in insulin treated nor in non-insulin treated patients. Albuminuria and renal function did not change. During captopril treatment one patient complained of a non-productive cough. Two patients experienced a severe hypoglycemic reaction during atenolol. No other major side-effects were seen. In conclusion, this study showed equal hypotensive effectivity of 100 mg captopril and 100 mg atenolol daily in hypertensive diabetics, without evident effect on glycemic control.

Diagnosing chronic fatigue syndrome: comparison of a protocol and computerised questionnaires.

BACKGROUND: In the context of outpatient care and within the framework of scientific research, guidelines and measuring instruments have been developed to help improve CFS diagnostics. The purpose of this study was to measure the agreement between the evaluations of chronically fatigued patients by physicians using a CFS protocol and by researchers using computerised questionnaires. METHODS: The sample consisted of 516 patients referred to an internal medicine outpatient clinic with complaints of chronic fatigue. Retrospectively the medical records and the computerised questionnaires were checked separately and compared to see whether the criteria for diagnosis of CFS had been met. In addition, the reasons for not diagnosing CFS were evaluated. RESULTS: Agreement between the physicians' and the researchers' evaluations was 84%. Disagreement mostly concerned severity of fatigue and functional impairment, or premorbid exclusion criteria. A physical cause for the chronic fatigue was only found in 3% of the cases. CONCLUSIONS: For physicians, questionnaire assessment may be complementary to the CFS protocol in optimising the process of diagnosing CFS.

Primary haemochromatosis: a missed cause of chronic fatigue syndrome?

OBJECTIVE: To determine whether patients previously diagnosed as chronic fatigue syndrome (CFS) actually have primary haemochomatosis (PH). METHODS: The setting was a Dutch referral centre. Transferrin saturation (TS) was retrospectively evaluated in banked blood samples of 88 patients diagnosed as CFS. Patients with elevated TS values were asked to provide a new overnight fasting blood sample for a second determination of TS and measurement of serum ferritin. The DNA was investigated for mutations in the HFE gene when one of these iron parameters was elevated. RESULTS: For 19 out of 88 patients with CFS an elevated TS was found. A new blood sample was obtained from 11 of these 19: six had increased TS and two had elevated serum ferritin values. These eight patients were neither C282Y homozygotes nor compound C282Y-H63D heterozygotes. In the eight cases where no new blood samples could be obtained, the TS was > 50% for two of the five men and < 45% for the three female patients. CONCLUSION: In a group of 88 CFS patients we could exclude PH in all but two of them (prevalence 2.3%; 95% confidence interval 0-5.5%). In our population of CFS patients PH is not more common than in a control population of northern European descent (prevalence 0.25-0.50%).

Normal carnitine levels in patients with chronic fatigue syndrome.

BACKGROUND: Patients with chronic fatigue syndrome (CFS) complain of muscle pain and impaired exercise tolerance. Previous studies show that this is due to systemic carnitine deficiency. We investigated the hypothesis that carnitine deficiency plays an important role in CFS in female CFS patients and compared their results with neighbourhood controls. METHODS: The level of total carnitine, free carnitine, acylcarnitine and carnitine esters were measured in 25 female CFS patients and 25 healthy matched neighbourhood controls in a blinded fashion. RESULTS: The previously reported decreased level of acylcarnitine in CFS patients was not confirmed. There were also no significant differences in levels of total carnitine, free carnitine and 20 carnitine esters between CFS patients and controls. CONCLUSIONS: The present study demonstrates that serum carnitine deficiency does not contribute to or causes the symptoms in many CFS patients.

[Chronic fatigue--'tired with 23 i's']. / Chronische vermoeidheid.'Moe met drieëntwintig oe's'.

Two patients, a woman aged 32 years and a man aged 49, presented with severe chronic fatigue. The woman had chronic fatigue syndrome; she recovered slowly. The man suffered from a pituitary adenoma producing follicle stimulating hormone; he recovered after transsphenoidal hypophysectomy. In patients with chronic fatigue, the history and a thorough physical examination to exclude underlying illness are very important; secondary symptom criteria must not be overemphasized (as is the case with the Holmes and Fukuda criteria), chronic fatigue syndrome should not be diagnosed if the condition has a shorter duration than 6 months, but it should be diagnosed if the clinical picture is compatible. The prognosis is not poor: in patients with a median disease duration of 4.5 years, 20% show significant improvement over an 18-month period.

[Life style intervention for patients with alcohol-related somatic problems]. / Leefstijlinterventie bij patiënten met alcoholgerelateerde somatische problemen.

Three patients suffered from somatic complaints related to excessive alcohol use. For the first patient, a 42-year-old man, the simple advice to quit drinking was enough for him to stop. A second patient, a 61-year-old woman, continued to deny drinking excessively despite several signs of excessive alcohol use. The third patient, a 45-year-old man, changed his drinking behaviour after receiving lifestyle intervention from the internist. All three patients needed a structural intervention to tackle the drinking problems in addition to medical treatment. The first lifestyle-intervention session takes 10 minutes and subsequent sessions take 5 minutes each. The intervention includes five elements: screening, placing on the agenda, inventory, making an appointment about change and reverting to the appointment about change. A trained nurse could also perform part of the intervention. Although lifestyle interventions seem to be expensive and time-consuming activities in the short-term, in the longer term they save time and money and lead to a satisfactory result for both the patient and physician.

[Diagnosis of 5 patients with possible primary hemochromatosis]. / Diagnostiek bij 5 patiënten met mogelijk primaire hemochromatose.

In a 49-year-old man and a 28-year-old woman, both of whom complained of fatigue, HFE-gen related respectively non-HFE-gen related primary haemochromatosis was diagnosed, based on the elevated serum transferrin saturation, the elevated serum ferritin levels, DNA studies and liver biopsy with qualitative respectively quantitative iron measurements. Their complaints diminished after bloodletting. Three women respectively 64, 61 and 46 years of age, were also suspected of primary haemochromatosis. The latter two presented with complaints of fatigue and malaise and chronic hepatitis C respectively. All three showed an elevated serum transferrin saturation and serum ferritin concentration. Further investigation showed the presence of secundary iron overload. Causes for it being excessive alcohol consumption, overweight and a poorly regulated diabetes mellitus type 2, and chronic hepatitis C respectively. These patients received specific therapy. Primary haemochromatosis is a common disorder of iron metabolism in individuals of Northern European descent. Diagnosis is based on an elevated serum transferrin saturation in combination with both elevated serum ferritin levels and homozygosity for the Cys282Tyr-mutation in the HFE-gen. The presence of an elevated serum transferrin saturation in combination with an elevated serum ferritin level is not always sufficient for the diagnosis, since these may be affected by other disorders. Moreover, iron overload may be caused by a form of haemochromatosis that is not HFE-related. In case of doubt as to the diagnosis, histological examination of the liver with a qualitative or quantitative iron determination is the golden standard.

Glycogenic hepatopathy: a rare cause of elevated serum transaminases in diabetes mellitus.

Glycogenic hepatopathy (GH) is a rare cause of serum transaminase elevations in type 1 diabetes mellitus (DM). We describe a 29-year-old woman with a history of poorly controlled type 1 DM who presented with hepatomegaly and severe transaminase flares. Liver histology confirmed GH, with glycogen accumulation due to severe fluctuations in both glucose and insulin. GH can be regarded as an adult variant of Mauriac's syndrome. Despite severe laboratory abnormalities, it does not cause liver cirrhosis. Treatment consists of improving glycaemic control.

Is increased erythrocyte sodium-lithium countertransport a useful marker for diabetic nephropathy?

Genetic predisposition to essential hypertension has been proposed as a risk factor for the development of diabetic nephropathy in type 1 (insulin-dependent) diabetes mellitus. An increased sodium-lithium countertransport activity (NaLiCT) has been suggested as a genetic marker for essential hypertension. We therefore evaluated NaLiCT in diabetic patients with (N = 39) or without (N = 23) diabetic nephropathy (DNP), patients with non-diabetic renal diseases (N = 42) and in healthy controls (N = 24). The NaLiCT was elevated in both diabetic patient groups compared to healthy controls (median 244; range 134 to 390 mumol.liter cells-1.hr-1), but was not different in patients with DNP (median 314; range 162 to 676), without DNP (median 325; range 189 to 627) and patients with non-diabetic renal disease (median 300; range 142 to 655). The genetic predisposition to DNP is illustrated by the fact that diabetic sibs of probands with DNP showed a higher occurrence of DNP than diabetic sibs of patients without DNP. We analyzed whether familial DNP clustered with an increased NaLiCT. The NaLiCT in sibs concordant for the presence of DNP (N = 10; median 307; range 217 to 428 mumol.liter cells-1.hr-1) was not significantly different from that in sibs concordant for absence of DNP (N = 15; median 279; range 189 to 442). We conclude that erythrocyte sodium-lithium countertransport activity cannot be used as a marker to identify patients at risk for the development of diabetic nephropathy.

Erythrocyte sodium-lithium countertransport is not different in type 1 (insulin-dependent) diabetic patients with and without diabetic nephropathy.

We studied erythrocyte sodium-lithium countertransport in 33 patients with Type 1 (insulin-dependent) diabetes mellitus with diabetic nephropathy, 18 patients with Type 1 diabetes without diabetic nephropathy and in 42 non-diabetic patients with various other renal diseases. No significant differences were found in sodium-lithium countertransport between these three groups (median (range) 322 (162-676) vs 321 (189-627) vs 300 (142-655) mumol.l cells-1.h-1). We conclude, that sodium-lithium countertransport cannot be used as a marker for diabetic nephropathy.

Body position and blood pressure measurement in patients with diabetes mellitus.

AIMS: World Health Organization (WHO) guidelines recommend that the blood pressure (BP) should be routinely measured in sitting or supine followed by standing position, providing that the arm of the patient is placed at the level of the right atrium in each position. The aim of our study was to test the influence of body and arm position on BP measurement in diabetic patients. METHODS: In 142 patients with diabetes mellitus the BP was measured using a semiautomatic oscillometric device (Bosomat-R): (i) after 5 min of rest sitting on a chair with one arm supported at the right atrial level and with the other arm placed on the arm support of the chair, (ii) after 5 min of rest lying on a bed with both arms placed on a bed, and (iii) after 30 s and after 2 min of standing with one arm (the same as in sitting position) supported at the right atrial level and with the other arm vertical, parallel to the body. RESULTS: Both systolic (SBP) and diastolic (DBP) blood pressures were significantly lower in sitting position with the arm at the right atrial level than in supine position (by 7.4 and 6.6 mmHg, respectively, P < 0.01). In sitting and standing positions, SBP and DBP were higher when the arm was placed either on the arm support of the chair or vertical, parallel to the body, than when the arm was supported at the level of the right atrium (by 6-10 mmHg, P < 0.001). Duration of standing did not influence the estimation of orthostatic hypotension. CONCLUSIONS: The data of this study indicate that the WHO recommendation with regard to the equivalence of sitting and supine BP readings is incorrect at least in diabetic patients, as the sitting BP is lower than the supine BP when the arm was positioned at the right atrial level. In addition, incorrect positioning of the arm in standing position results in an underestimation of prevalence of orthostatic hypotension. We conclude that during BP measurement the arm should be placed at the right atrial level regardless of the body position.

Relevance of erythrocyte Na+/Li+ countertransport measurement in essential hypertension, hyperlipidaemia and diabetic nephropathy: a critical review.

In this review the usefulness of the measurement of erythrocyte Na+/Li+ countertransport (Na+/Li+ CT) activity is evaluated. In particular, the association between enhanced erythrocyte Na+/Li+ CT activity and essential hypertension, hyperlipidaemia and diabetic nephropathy is discussed. The conclusion of this review is that elevated erythrocyte Na+/Li+ CT activity is associated with essential hypertension and hyperlipidaemia. A relationship between Na+/Li+ CT activity and diabetic nephropathy is less evident. Despite a significant link of Na+/Li+ CT activity with hypertension and hyperlipidaemia, the diagnostic significance of Na+/Li+ CT activity is low. This is due to the large overlap between the results of control subjects and patients. The factors that contribute to this broad range are discussed in detail.

Captopril acutely lowers albuminuria in normotensive patients with diabetic nephropathy.

Angiotensin-converting enzyme (ACE) inhibitors decrease albuminuria in patients with diabetic nephropathy. To study the change in albuminuria in relation to changes in systemic and renal hemodynamics, nine normotensive patients with type 1 (insulin-dependent) diabetes mellitus and persistent proteinuria were given a single oral dose of 25 mg of the ACE inhibitor captopril. Blood pressure, glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and albumin excretion rate (AER) were measured in two periods of 40 minutes before and in four periods of 40 minutes after administration of captopril. A constant water diuresis was maintained. Blood pressure did not decrease significantly (130/79 +/- 4/3 v 124/74 +/- 4/3 mm Hg; mean +/- SEM), median AER decreased from 403 (interquartile range [IQR], 812) micrograms/min to 333 (707) micrograms/min (P < 0.01). GFR did not change (123 +/- 13 v 117 +/- 14 mL/min), but ERPF increased significantly from 609 +/- 56 to 714 +/- 55 mL/min (P < 0.01). Consequently, the filtration fraction (FF; quotient of GFR and ERPF) decreased from 0.20 +/- 0.014 to 0.17 +/- 0.014 (P < 0.01). A strong correlation was found between the decrease of AER and the decrease of FF (rs = 0.75; P < 0.02). No correlation was found between the decrease in AER and changes in GFR or blood pressure. In the normotensive patient with diabetic nephropathy, captopril causes an acute reduction of AER, which is probably mediated by a lowering of the intraglomerular pressure.

Captopril and atenolol are equally effective in retarding progression of diabetic nephropathy. Results of a 2-year prospective, randomized study.

The progression of diabetic nephropathy can be positively influenced by maintaining a low blood pressure level. This has been shown in studies with conventional antihypertensive treatment as well as with ACE inhibitors. Whether the latter group of drugs is more effective remains to be proven and was the aim of our study. In a prospective randomized study we compared the effects of ACE inhibition and beta-blockade on retarding progression of renal function in IDDM patients with an early stage of overt diabetic nephropathy. Twenty-nine patients were studied for 2 years, 15 were randomized for treatment with captopril and 14 for atenolol. Every 6 weeks blood pressure and urinary albumin and total protein excretion were measured. GFR was measured every 6 months as 51Cr-EDTA clearance. Baseline values for blood pressure, renal function and albuminuria were identical in the two groups. The effect of both drugs on blood pressure was not significantly different. In the captopril-treated patients MAP before and after 2 years was 110 +/- 3 (SEM) and 100 +/- 2 mm Hg, respectively and in the atenolol-treated patients 105 +/- 2 vs 101 +/- 2 mm Hg. Both drugs reduced albuminuria and total proteinuria to the same extent. With captopril albuminuria decreased from 1549 (989-2399) to 851 (537-1380) mg/24 h and proteinuria from 2.5 (1.6-3.8) to 1.2 (0.8-1.8) g/24 h. With atenolol albuminuria decreased from 933 (603-1445) to 676 (437-1047) mg/24 h and proteinuria from 1.5 (1.0-2.4) to 0.9 (0.6-1.5) g/24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Sodium-lithium countertransport is increased in normoalbuminuric type 1 diabetes but is not related to other risk factors for microangiopathy.

BACKGROUND: It has been reported that sodium-lithium countertransport (Na/Li CT) activity is increased in patients with diabetes mellitus and that this increased Na/Li CT activity is associated with the development of diabetic nephropathy. It is unclear however, whether Na/Li CT is related to other pathophysiological factors in diabetic patients. We studied kinetic parameters of Na/Li CT activity together with other putative risk factors for microangiopathy in normoalbuminuric type 1 diabetic patients and matched control subjects. SUBJECTS AND METHODS: We measured maximum velocity (Vmax) and sodium affinity (Km) of Na/Li CT in 53 diabetic patients and 45 healthy controls. Endothelial function was assessed by monitoring forearm vascular response to intrabrachial infusion of acetylcholine. Blood samples were collected for measurement of HbA1c, glucose, insulin and lipids. Blood pressure was measured intra-arterially. Renal haemodynamics were measured by inulin/p-aminohippurate clearance. Urinary albumin was measured by enzyme-linked immunosorbent assay. Transcapillary escape of albumin (TERalb) was calculated by the disappearance curve of 125I-labelled albumin. RESULTS: Vmax was increased in diabetic patients (779 +/- 36 micromol Li+ h-1 L-1 erythrocytes vs. 623 +/- 35 in controls, P < 0.01), whereas Km was decreased (64 +/- 16 mmol L-1 vs. 76 +/- 27 in controls, P = 0.03). The ratio of Vmax : Km was 12.4 +/- 0.6 in diabetic patients and 8.9 +/- 0.9 in controls (P < 0.001). When comparing diabetic patients in the lowest and highest quartile of Vmax or Km there were no differences in blood pressure, renal haemodynamics, urinary albumin excretion, TERalb, endothelial function, HbA1c, glucose, insulin, or lipid profile. CONCLUSION: Na/Li CT is increased in uncomplicated type 1 diabetes and characterized by an increase in Vmax and a decrease in Km. The increase in Na/Li CT is not associated with changes in endothelial function, degree of metabolic control, blood pressure or renal haemodynamics.