Strict Glucose Control Research Articles

Epinephrine Secretion, Hypoglycemia Unawareness, and Diabetic Autonomic Neuropathy

The failure of some type I diabetic patients to secrete epinephrine and glucagon in response to hypoglycemia has been documented by many investigators, and most studies have confirmed that an inability to secrete these counterregulatory hormones places patients at risk for developing clinical hypoglycemia. Inadequate acute glucose counterregulation can result from multiple mechanisms. Failure of central glucoreceptors to recognize hypoglycemia and to activate counterregulation may be the most common. Decreased central recognition of hypoglycemia results from either strict antecedent glucose control or from a recent hypoglycemic event. Controversy about the relation between autonomic neuropathy and counterregulatory hormone secretion has arisen because divergent criteria have been used in the published studies for the diagnosis of autonomic neuropathy. Advanced adrenergic neuropathy, as evidenced by orthostatic hypotension, generally leads to decreased epinephrine secretion after hypoglycemia. Subclinical neuropathy, however, as diagnosed from measurement of heart rate variability, may diminish the awareness of hypoglycemia but does not affect counterregulatory hormone secretion. Failure of counterregulatory hormone secretion in some patients with type I diabetes, however, may represent a selective autonomic neuropathy; the disease has limited the patient's ability to secrete epinephrine and pancreatic polypeptide in response to hypoglycemia even though it has spared the autonomic neurons responsible for cardiovascular reflexes. Finally, recent provocative reports indicate that decreased responsiveness to adrenergic stimuli may cause hypoglycemia unawareness in some patients. Further documentation of this mechanism is required, and its relative importance with respect to other mechanisms needs to be established. These questions are increasingly important clinically because the Diabetes Control and Complications Trial has confirmed that the prevalence of severe hypoglycemia remains a major obstacle to attempts to prevent diabetic complications with intensive insulin therapy. Until glucose counterregulation is more fully understood and methods for preventing hypoglycemia developed, patients with recurrent hypoglycemia unawareness or a history of hypoglycemia-related accidents should probably not be treated with intensive insulin therapy.

Glucose clamp investigations. The ups and downs.

With the results of the Diabetes Control and Complications Trial (DCCT) now known (1), health-care providers are faced with the task of implementing more strict glucose control in diabetic patients. Yet, the methodology on the safest way to complete this change in health-care delivery is far from crystallized. Epidemiological data from the DCCT strongly suggest that hypoglycemia begets hypoglycemia (2). Over half of the severe hypoglycemie episodes occurred without warning signs. The importance of understanding the pathophysiological mechanisms behind this disturbing excess of morbidity is clear.

Management dilemmas in the individual with cystic fibrosis and diabetes

As their life expectancy has improved, patients with cystic fibrosis (CF) have experienced an increasing incidence of diabetes. Hyperglycemia may adversely influence weight, pulmonary function, and development of microvascular complications. Strict control of blood glucose has not universally been sought, however. A program of multiple daily insulin injections and self-monitoring of blood blucose with an aim of normoglycemia is described in this article. The typical cystic fibrosis diet is variable in quantity and features a preponderance of simple carbohydrates; this is contrary to the usual diabetes meal plan. We describe the use of a flexible meal-planning system to establish individualized carbohydrate targets with specific insulin boluses titrated to each meal to control postprandial blood glucose excursions. Records of 22 patients followed for more than 1 year are reviewed. Mean (±standard error of the mean) glycosylated hemoglobin was reduced from 11.3±3.1% (at baseline) to 8.1±1.8% (at 1 year). Mean percent of ideal body weight also increased from 95.4±15.2 to 100±17.1. We conclude that strict metabolic control is an attainable goal in patients with cystic fibrosis and is associated with positive weight gain.

Postnatal Glucose Kinetics in Newborns of Tightly Controlled Insulin-Dependent Diabetic Mothers

Infants of diabetic mothers are at risk of developing hypoglycemia postnatally. Strict control of blood glucose during pregnancy might result in adequate glucose homeostasis in the neonate. We followed 15 mother-infant pairs from the beginning of pregnancy until birth. Glucose kinetics in the infants were measured on the first day of life, using a stable isotope dilution technique. Furthermore, levels of alternative substrates, FFA, and ketone bodies were measured. All infants received i.v. glucose from birth onward at a rate of 3.4 +/- 0.7 mg/kg/min (mean +/- SD). There was no relationship between the parameters of control of the insulin-dependent diabetes mellitus in the mothers and glucose kinetics in their infants. Glucose turnover was 5.2 +/- 1.1 mg/kg/min, glucose production rate (GPR) was 1.8 +/- 1.1 mg/kg/min. GPR was significantly lower in the infants studied at the end of the first day of life (p < 0.01), irrespective of the glucose infusion rate. Furthermore, the lower GPR was associated with an increased concentration of ketone bodies, suggesting an increased production of ketone bodies in these infants. The relatively high GPR measured in the infants who were studied in the first hours postnatally may be the result of postnatal hormonal stimulation of glycogenolysis and/or gluconeogenesis. From this study, we conclude that glucose kinetics in infants of tightly controlled diabetic mothers appear to be normal. Interestingly, despite the near-optimal insulin therapy in the mothers, there is a relationship between the SD scores of birth weight and the mean 3rd-trimester blood glucose values.

Diabetic Renal Disease in Type 1 Diabetes: Aetiology and Prevention

Diabetic renal disease affects a subset of about 35% of patients with Type 1 diabetes and is characterized by a triad comprising increased albuminuria, arterial pressure, and volume fraction of the mesangium. This leads to a decline in the glomerular filtration rate and ultimately end-stage renal failure or premature cardiovascular mortality. Individuals at risk can be detected before the development of persistent proteinuria by screening for microalbuminuria which has proved predictive of clinical nephropathy in about 80% of cases. Microalbuminuria is often accompanied by subclinical increases in arterial blood pressure and plasma lipid levels and is usually not apparent until 5 years after stabilization of newly diagnosed diabetes. This latter finding suggests that microalbuminuria is an indicator of early disease rather than a marker of susceptibility to it. Recent evidence suggests that diabetic renal disease may be linked to a familial, possibly genetically determined, predisposition to arterial hypertension or to some factor closely related to the risk of hypertension. This underlying predisposition may be one of the mechanisms leading to severe glomerular damage and may help to explain why clinical renal disease only occurs in a subset of diabetic patients. A number of therapeutic interventions, ranging from strict blood glucose control to low-protein diet and angiotensin-converting enzyme inhibition are effective in reducing or preventing further increases in microalbuminuria. If current long-term trials confirm that treatment of microalbuminuric diabetic patients prevents the onset of heavier persistent proteinuria secondary prevention of diabetic renal failure may become possible. The current criteria for diagnosis of diabetic nephropathy will then require revision.

Does intensive glycemic control in diabetic pregnancies result in normalization of other metabolic fuels?

Intensive treatment of insulin-dependent diabetes mellitus during pregnancy often normalizes plasma glucose levels. However, it is unclear whether this adversely affects other metabolic fuels that are essential to normal fetal growth and development. Metabolic studies were conducted after the subjects ingested a standardized mixed meal during each trimester in 7 normal and 15 insulin-dependent diabetic pregnant women. The latter were treated with continuous subcutaneous insulin infusion or multiple injections, which were adjusted to achieve strict glucose control throughout pregnancy. Insulin, alanine, branched-chain amino acids, triglycerides, free fatty acids, and ketones were measured every 15 to 30 minutes before a standardized breakfast and for 150 minutes after the breakfast. Patients with insulin-dependent diabetes mellitus were studied while they received their unusual insulin dosages. Fasting glucose levels (87 +/- 7 mg/dl) and glucose levels 150 minutes after the meal (112 +/- 11 mg/dl) were near normal. However, normoglycemia was achieved at the expense of increased plasma insulin levels (area under insulin response curves, p less than 0.01, vs nondiabetic curves). Nevertheless, fasting and post-prandial plasma branched-chain amino acids, alanine, and free fatty acids were similar in both groups. Fasting cholesterol, triglyceride, and ketone levels were also normalized. We conclude that normalization of circulating amino acids and lipids in conjunction with correction of hyperglycemia may contribute to favorable outcomes in infants of intensively treated diabetic mothers.

Enteral Hyperalimentation with Continuous Subcutaneous Insulin Infusion Improved Severe Diarrhea in Poorly Controlled Diabetic Patient

Little is known about effective treatment for severe diarrhea in the insulin-dependent diabetic patient. A 41-year-old woman was admitted to our hospital because of hyperglycemia and dysuria. She had stopped insulin self-injection therapy for 2 years and diarrhea had become worse, resulting in malnutrition. Following enteral alimentation by elemental diet (ED) with continuous subcutaneous insulin infusion (CSII), frequency of diarrhea remarkably decreased and general nutritional condition was improved. At the first step, the patient was given 600 kcal/d ED through the tube sustained in the jejunum. Total calorie intake for 24 hours was gradually increased to the level of 2400 kcal/d and this therapy continued for 5 months. During this period, blood glucose level was kept in almost normal range (between 100 and 200 mg/dL) through the continuous insulin infusion of regular insulin (1.0-1.5 U/h). Thereafter, general conditions were improved and frequency of diarrhea gradually decreased. When this treatment was stopped, watery diarrhea, steatorrhea, and hypoalbuminemia completely disappeared and she gained 12 kg of body weight. Furthermore, spontaneous urination appeared following this treatment. This case suggests that the enteral hyperalimentation combined with strict control of blood glucose, using the CSII, may be an effective therapy for such severe diarrhea with malnutrition in diabetes.

Emphysematous cystitis: A complication of urinary tract infection occurring predominantly in diabetic women

The case of a patient with emphysematous cystitis who presented with complaints of lower abdominal pain, dysuria, and pneumaturia is presented. The presenting symptoms, differential diagnosis, and radiographic and cystoscopic appearances of emphysematous cystitis, a rare complication of lower urinary tract infection occurring almost exclusively in diabetics, are reviewed. Treatment consists of urinary drainage, prompt initiation of antibiotic therapy, and strict glucose control. The prognosis usually is excellent.

Schwangerschaftsausgang unter intensivierter Insulintherapie bei manifestem Diabetes*

In 1981, the intensified insulin therapy for achievement of euglycaemia in pregnant diabetics was introduced at the University Department of Obstetrics and Gynaecology in Cologne. This study compares the results of 112 pregnancies in women with overt diabetes monitored before (1971-1980) or after (1981-1988) changing the therapeutic regimen. In the period from 1981 to 1988, the proportion of euglycaemic patients (preconceptionally 19%, before delivery 79%) was clearly higher than from 1971 to 1980 (n = 42; 7% and 9%, respectively). The tight blood glucose control resulted in a doubling of hypoglycaemic episodes during pregnancy. The proportion of preterm deliveries was reduced from 47% to 24%. The rate of caesarean sections was nearly constant (1971-1980: 38%, 1981-1988: 34%). The marked success of therapy was the decrease of perinatal mortality from 20.9% to 2.9%. The perinatal morbidity also diminished, as shown by the decreasing rates (30-90%) of foetopathy, macrosomy, respiratory distress syndrome, birth trauma, hypoglycaemia, hypocalcaemia and polycythaemia. The malformation rate, however, remained high (1971-1980 = 7%, 1981-1988 = 11%). The results demonstrate the necessity of a strict blood glucose control during pregnancy, beginning before the time of conception.

Value of Strict Control of Blood Pressure and Glucose in Diabetics with ESRD

On November 15, 1988 Eli A. Friedman spoke at a meeting of the Nephrology Society of New Jersey on the topic, Interventional Strategies in Diabetic Nephropathy. The following exchange of letters took place following that talk They are reprinted here because they were felt to be of interest to our readers.

Symptomatic Hypoglycaemia in Childhood Diabetes: A Population‐Based Questionnaire Study

The occurrence of severe and mild hypoglycaemic attacks and their symptoms and signs were studied in 92 insulin-dependent diabetic children, 7-18 years old. A questionnaire was distributed to all families and they were interviewed by an experienced nurse. Severe attacks, for which the help of an adult was needed, were reported by 44% of the children during a 12-month period. Thirty-seven per cent of the attacks occurred in the mornings, most often attributed to extra physical exercise, but equally often without any obvious cause. They were more common in children with strict blood glucose control measured as HbA1c. Fast-acting carbohydrates, given by parents, relieved the attack in most children, but 15% needed a glucagon injection and 12% intravenous glucose. In all, 16% were admitted to hospital. Mild events occurred in 97% of the children, at least once per week in 53% of the children, and were not related to blood glucose control. They were often attributed to extra physical exercise and occurred mainly between breakfast and lunch. Initial symptoms were tremor and hunger; during the whole event tremor and sweating were most common. Parents noted pallor as the most common sign. The frequency of severe or mild attacks could not be correlated to the age of the child, duration of diabetes, daily dose or number of insulin injections.

Interventions Based on Microalbuminuria Screening and Low-Protein Diet in the Treatment of Kidney Disease of Diabetes Mellitus

Microalbuminuria in insulin-dependent diabetics appears to indicate early renal damage rather than susceptibility to it, yet a series of relatively small, short-term intervention studies in insulin-dependent diabetes mellitus patients have already demonstrated reduction in albumin excretion rates or arrest in the increase of fractional clearance of albumin. Treatments have ranged from the use of angiotensin-converting enzyme inhibitors aimed at lowering BP to the use of diets restricted to 0.5 to 0.6 g/kg protein and strict blood glucose control by intensified insulin treatment. Large, long-term intervention studies of cohorts of insulin-dependent and non-insulin-dependent diabetic patients with microalbuminuria are now needed to assess the effects of the different modalities of care on the development of persistent proteinuria, end-stage renal disease, and cardiovascular mortality as well as associated quantitative changes in the renal structure.

Optimizing blood glucose control in type 2 diabetes: an approach based on fasting blood glucose measurements.

A structured approach to the management of Type 2 diabetes, aiming to reduce fasting blood glucose levels to near-normal, can provide effective blood glucose control with minimal risk of hypoglycaemia and in a manner acceptable to most patients. When the fasting blood glucose value is maintained in the region 4-6 mmol l-1, protein glycosylation and plasma triglyceride values usually become near-normal and this may help to prevent the development of long-term diabetic complications. We propose a simple management strategy, based on 3-monthly fasting blood glucose determination, which uses not more than two therapeutic agents at any one time. If diet and maximal oral therapy fail to keep fasting blood glucose levels below 6 mmol l-1 then the addition of a basal insulin supplement, e.g. from a once daily injection of ultralente insulin, can restore near-normal fasting blood glucose levels without the need for full insulin replacement therapy. In older patients, where long-term prevention of diabetic complications is not such an immediate priority, less strict blood glucose control may be reasonable, aiming to keep the fasting blood glucose values below 10 mmol l-1 in order to prevent symptoms secondary to glycosuria. Patients can be seen at a monthly general practice morning diabetic mini-clinic or with the aid of a nurse visiting elderly patients at home.

Protein restriction, blood pressure and the progression of diabetic nephropathy.

Diabetic nephropathy is the long-term complication of diabetes responsible for the greatest increased mortality. Clinical nephropathy is characterised by a triad consisting of persistent proteinuria (total urinary protein greater than 0.5 g/24 h), rising arterial pressure and declining renal function. The role of treatment of raised blood pressure and the influence of dietary protein restriction on the established progressive phase of the disease are discussed. Subclinical elevations of urinary albumin excretion rates (greater than 30 micrograms/min; microalbuminuria), glomerular hyperfiltration and marginal elevations of arterial pressure are early markers of later clinical nephropathy which appear to respond to strict blood glucose control, blood pressure treatment and lowered dietary protein intake. Recent evidence to suggest that an inherited predisposition to raised arterial pressure may confer the susceptibility to diabetic nephropathy is presented.

Correlation of renal histopathology duration of diabetes, and control of blood glucose in patients with type II diabetes

Correlations of renal histopathologic changes, duration of diabetes, and the degree of control of blood glucose in patients with diabetic nephropathy were determined. Biopsies from 17 patients with diabetic nephropathy due to Type II diabetes were examined. Mild histopathologic changes in renal tissues were observed in patients with good blood glucose control, even if their disease was of more than 5 years' duration. Moderate to severe renal histopathology was found in patients with poor blood glucose control regardless of the duration of diabetes. It is concluded that strict control of blood glucose during the course of diabetes is important in inhibiting the progression of renal involvement in patients with Type II diabetes.

Maternal residual beta-cell function and the outcome of diabetic pregnancy.

Preservation of own insulin production (residual pancreatic beta-cell function) has been shown to have a beneficial effect on glycemic control in insulin-dependent diabetic subjects, and its total lack has been suggested to be an independent risk factor during diabetic pregnancy. We studied the influence of residual beta-cell activity on the glucose control and the outcome of pregnancy in 29 diabetic women by sequentially measuring gestational postprandial plasma C-peptide (CPR) levels, diurnal blood glucose curves and blood glycosylated hemoglobin (Hb A1c) and by analyzing the morbidity and mortality of the offsprings. The 9 diabetics with moderate own insulin secretion (CPR levels over 1.0 microgram/l, White classes B and C, later referred to as group I) had significantly better glucose control than the remaining 20 subjects with lower CPR values (White classes C, D and NF, later referred to as group II) (figure 1, table I). There were two intrauterine deaths, both in group II. These deaths (one caused by multiple congenital contracture syndrome and the other by severe intrauterine growth retardation without any evident cause) could not be straightly connected with diabetes. Respiratory distress syndrome was seen in group II only. There was no other significant difference in the neonatal morbidity between the two groups (table II). All mothers of RDS infants were in White class NF where the birthweight was also smaller than in classes B and C. These were the only differences in neonatal morbidity between the White classes (table III). In conclusion, moderate residual beta-cell function seemed to be clinically important in maintaining strict glucose control during gestation.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of ischemia on peripheral nerve function in diabetes mellitus

In Japan, diabetic patients are known to be able to sit on the floor for a prolonged time because of mildness or absence of ischemic paresthesia. In order to investigate this resistance to ischemia quantitatively, the mixed nerve function of the median nerve was studied during 30 min of ischemia using surface electrodes in 60 diabetic patients and 15 normal subjects. In studies of 33 unequivocal diabetics, potential amplitudes decreased during ischemia more slowly than in the controls, and at 15 min of ischemia, potential amplitudes were greater in all 33 diabetics than in the 15 normal subjects. The relationship between the resistance to ischemia and various aspects of diabetes was studied further in the 60 diabetics including the 33 aforementioned patients. Resistance to ischemia was found in almost all diabetics and no significant correlation was shown with values for fasting blood glucose and HbA1c, other diabetic complications or duration of diabetes. However, values for potential amplitudes declined to the normal range in seven of 18 patients after strict glucose control. These results suggest that resistance to ischemia is the earliest manifestation of peripheral nerve dysfunction and is different from classical diabetic neuropathy. Furthermore, the method employed in this study is simple, noninvasive and clinically very useful.

Severe hypoglycemia during pregnancy: Its frequency and predisposing factors in diabetic women

Severe hypoglycemic episodes, as defined as altered consciousness to the extent that self treatment is impossible, were sought prospectively in pregnant diabetic women. One or more episodes were found in none of 21 gestational onset, insulin-requiring women during their 28 pregnancies but were present in 19 (33%) of the 57 already insulin dependent (Type 1) women during 26 (36%) of their 72 pregnancies. The most common predisposing factors included strict glucose control, anorexia, early morning hours (1200-0900), lack of an adrenergic response and time shortly before the next anticipated meal.

Effets du pancreas artificiel sur les fonctions nerveuses peripheriques chez le diabetique

Twenty-one diabetic subjects were studied; all manifested fasting hyperglycemia and elevated Hb A1C. Motor conduction velocity of the median, ulnar and peroneal nerves; F wave of the peroneal nerve; sensory conduction velocity and sensory potential amplitude of the median and ulnar nerves and H reflex were determinated immediately before and after two days of strict glucose control with an artificial endocrine pancreas. A significant and acute improvement of some electrophysiological parameters led us to presume that repair of structural lesions would be unlikely. Only a metabolic disturbance, due to hyperglycemia, can be rapidly corrected.

Increased nerve conduction in diabetics after a year of improved glucoregulation

We studied median, ulnar and peroneal motor nerve conduction velocity (NCV) and median sensory action potential (SAP) latency and amplitude in 18 insulin-dependent diabetic patients who were begun on a continuous subcutaneous insulin infusion (CSII) program. With institution of this therapy, significant decreases in mean blood glucose and glycosylated hemoglobin occurred. After 12 months of CSII treatment, median, peroneal, and ulnar motor NCVs all increased significantly. The average NCV increase was 2.5 m/s. Median SAP amplitude and latency did not significantly change. In a second group of 12 diabetic patients with the same mean age and comparable initial NCV and SAP measures, no significant changes in motor NCVs or SAPs occurred after 12 months of conventional insulin treatment. These results indicated the need for further long-term studies of the role of strict glucose control in the prevention of diabetic neuropathy.