Insulin therapy for type 2 diabetes: premixed or basal-prandial?

It is logical to begin type 2 insulin therapy with an injection of an intermediate-acting or a long-acting insulin at bedtime, but one should treat to target, i.e. aim at fasting glycaemias lower than 1.20 g/l to obtain an HbA(1c) close to 7%. Nevertheless, basal insulin therapy does not prevent progression to insulin-secretory deficiency. If necessary, recourse should be made to multiple-injection protocols, taking into account postprandial hyperglycaemia. For every level of HbA(1c), the suppression of postprandial hyperglycaemia, 1 point of HbA(1c) can be gained in theory, whereas reducing the fasting glycaemia to values of less than 1.10 g/l reduces HbA(1c) to close to 7%, whatever the initial level of HbA(1c). However, when a diabetic is clearly not controlled, the preprandial acting use of rapid analogues allows the fasting glycaemia to be improved significantly. Inversely, an early treatment with basal insulin, by correcting glucotoxicity, can also decrease postprandial hyperglycaemia. Many industry-sponsored studies comparing insulin therapy regimens show annoying biased interpretations of results. It does not seem pertinent to compare a single injection with two or even three injections, nor to compare an efficient titration with an inefficient titration or to eliminate oral drugs, in particular sulphonylureas combined with a basal insulin. If premix insulins can give satisfactory results in patients who maintain a sufficient residual insulin-secretion, we think it would be preferable to adopt the basal-prandial regimen and a step-by-step escalating therapy. The first stage consists in combining oral therapy with an injection of NPH insulin or a long-acting analogue at bedtime, aiming at a fasting glycaemia of less than 1.20 g/l. In the next stages, a single injection of rapid-acting insulin analogue is added each time. The main advantage of this regimen is to fix a target adapted to each injection and, as a result, to facilitate forced titration of the doses.

Hypoglycemic symptoms and decreased beta-adrenergic sensitivity in insulin-dependent diabetic patients.

Thirty-seven insulin-dependent diabetic patients were tested for symptoms of hypoglycemia, cardiac autonomic neuropathy (i.e., heart rate variation during deep breathing, Valsalva maneuver, immediate heart rate response to standing), and isoproterenol sensitivity (defined as the dose of isoproterenol required to increase heart rate by 25 beats/min: I25). Tests of cardiac autonomic neuropathy showed no relation to hypoglycemic symptoms. On the contrary, a clear relationship could be established between isoproterenol sensitivity and adrenergic symptoms of hypoglycemia. Diabetic patients with decreased response to isoproterenol had fewer adrenergic symptoms, perceived hypoglycemia at a lower blood glucose level, and had more hypoglycemic accidents. Symptoms most related to isoproterenol sensitivity were tremor, sweaty palms, and hunger. With the isoproterenol-sensitivity test a distinction could be made between the groups at high (I25 greater than 3 micrograms) and low (I25 less than 3 micrograms) risk for hypoglycemic accidents. We suggest that the isoproterenol-sensitivity test could be used to identify diabetic patients at increased risk for hypoglycemia.

Phobic symptoms, particularly the fear of blood and injury, are associated with poor glycemic control in type I diabetic adults.

OBJECTIVE: To investigate the presence of psychiatric disorders and symptoms in type I diabetic patients and to identify those that may influence metabolic control as assessed by GHb levels. RESEARCH DESIGN AND METHODS: This was a cross-sectional study. One hundred and two consecutive patients with type I diabetes who were regular outpatient visitors of a diabetology department were evaluated. The psychiatric assessments included self-rating questionnaires (General Health Questionnaire and Fear Questionnaire) and observer-rating questionnaires (Montgomery-Asberg Depression Rating Scale [MADRS] and Mini International Interview). Diabetic characteristics were assessed by a structured interview. The observer was blind to the diabetic characteristics of the patients. RESULTS: Type I diabetic patients with GHb levels > or = 8% had higher psychological distress, scored significantly higher for symptoms of agoraphobia and for fear of blood and injury, had substantially higher levels of anxiety-depression, and performed significantly fewer blood glucose measurements per day. They did not differ in MADRS score from patients with GHb levels < 8%. Multivariate analysis showed that GHb was positively associated with the total score of phobic symptoms and the level of anxiety-depression and inversely associated with the number of daily blood glucose measurements. These factors explained 41% of the variance of GHb. The inverse relationship between GHb and the number of blood glucose measurements per day was mainly influenced by the fear of blood and injury. Patients with high scores for the fear of blood and injury performed fewer blood glucose measurements and had poorer glycemic control; conversely, subjects without fear of blood and injury performed more daily blood glucose measurements and had better glycemic control. CONCLUSIONS: Phobic symptoms are frequent in patients with type I diabetes. The intensity of phobic symptoms and anxiety-depression negatively influences metabolic control. Increased fear of blood and injury may lead some patients to perform few home blood glucose measurements and may result in poorer glycemic control. This suggests that, by decreasing the fear of blood, injury, and injection, metabolic control may be improved.

Decreased beta-adrenergic sensitivity in insulin-dependent diabetic subjects.

To study beta-adrenergic sensitivity in diabetes mellitus, we performed isoproterenol sensitivity tests in 34 insulin-dependent diabetic patients and 10 age-matched normal subjects. beta-adrenergic sensitivity [defined as the dose of isoproterenol required to increase the resting heart rate by 25 beat/min, (I25)] was significantly higher in the diabetic group (4.07 +/- 1.4 micrograms, mean +/- SD) than in the normal group (2.02 +/- 1.49 micrograms). A comparison of I25 of normal subjects and diabetic patients as a function of age showed that the latter were significantly less sensitive to beta-adrenergic stimulation at all ages (P less than 0.01). In diabetic patients, beta-adrenergic sensitivity also increased with the duration of diabetes (r = 0.64, P less than 0.0005), but the correlation was stronger when the age of the patients and the duration of the diabetes were both taken into consideration (r = 0.72, P less than 0.0005). We conclude that beta-adrenergic sensitivity is diminished in patients with type I diabetes mellitus of all ages.

How type 1 diabetic patients with good or poor glycemic control cope with diabetes-related stress.

OBJECTIVE: To determine the link between glycemic control and the strategies adopted by patients in coping with diabetes-related stress. MATERIAL AND METHODS: In a cross-sectional study of 122 type 1 diabetic patients, glycemic control was evaluated on the basis of the last mean annual HbA(1c) level, and a comparison was made of two groups of patients, i.e., those with "good control" (HbA(1c)<7.5%) and "poor control" (HbA(1c) > 8.5%). Sociodemographic were collected for all patients by the referring physician. The nature of the diabetes-related stress and the coping strategies adopted by patients were determined by analyzing validated self-assessment questionnaires. RESULTS: Comparison showed that there was no significant difference between the two groups in terms of the patients' age, level of education, age at onset, duration of the diabetes, or the nature of diabetes-related stress factors. In contrast, the difference between the groups was significant in that patients in the "well controlled" group carried out more home blood glucose tests (p<0.02), had fewer complications (p<0.003), and made greater use of so-called "task oriented" strategies (p=0.023), regardless of the existence of any complications. CONCLUSIONS: Even though the nature of the diabetes-related stress appears to be the same for the two groups, type 1 diabetic patients with good glycemic control manage their condition differently (more frequent home blood glucose tests) and use coping strategies that place greater emphasis on problem solving.

Propranolol in hypoglycaemia unawareness.

The effect of propranolol on the occurrence of hypoglycaemic symptoms was assessed in insulin-dependent diabetic patients with hypoglycaemia unawareness. A double-blind, randomised parallel group study (2:1 fashion) was conducted over 4-week period. The propranolol group (n = 9) received 20 mg (week 1 and 2) and 30 mg (week 3 and 4) twice daily, and the other group (n = 5) a matched placebo for 4 weeks. Patients included had experienced at least two severe hypoglycaemic episodes (coma or seizures) during the previous year, which were characterised by a lack of adrenergic symptoms and required the assistance of another person. The mean number of hypoglycaemias during the study period was similar in both groups (placebo: 13 +/- 2 propranolol: 11 +/- 1), whereas the number of totally asymptomatic hypoglycaemias (< 0.6 g/l) was lower on propranolol than on placebo (3 +/- 1 vs 8 +/- 3, NS) and the number of symptomatic hypoglycaemias was higher (7.2 +/- 2 vs 4.6 +/- 1, NS). Subjective evaluation of treatment by the investigators showed 0/5 successes in the placebo group and 5/9 in the propranolol group (chi2 = 4.32, p = 0.038). The main advantage of propranolol over placebo was an increased incidence of sweating. The ratio [number of hypoglycaemias with sweating/total number of hypoglycaemias] being higher with propranolol (0.28 +/- 0.08 vs 0.06 +/- 0.02, p = 0.06). This pilot study suggests that beta-blockers may be useful in restoring adrenergic symptoms during hypoglycaemia in insulin-dependent diabetic patients without warning symptoms of hypoglycaemia. This beneficial effect seems to be predominantly related to an increase in hypoglycaemia-induced sweating. A larger study is needed to confirm or invalidate these preliminary results.

Relevance of measuring red blood cell disaggregability in insulin-dependent diabetic patients.

A viscometric study of blood from insulin-treated diabetic patients is carried out. Patients are divided into three major groups--group I: without or with minimal retinopathy and recent diabetes (n = 37), group II: without or with minimal retinopathy and at least 20 years of diabetes duration (n = 35), group III: with severe retinopathy (n = 27). Each group is also subdivided according to the glycosylated hemoglobin (HbA1c) level, used to assess long-term glycemic control. Finally, the rheological parameters of six groups are compared: three of which have a HbA1c level less than 7.5% [I1 (n = 15), II1 (n = 9), III1 (n = 9)] and three others have a HbA1c level more than 7.5% [I2 (n = 22), II2 (n = 26), III2 (n = 18)]. The most important result concerns the thixotropy index xi t, which reflects the dynamic property of red blood cell (RBC) disaggregability under shear. Strong correlations between this parameter and HbA1c level are found for groups I (r = -0.53, p < 0.001) and III (r = -0.68, p < 0.001), providing evidence of a RBC disaggregability disorder for a poor glycemic control of diabetes. In contrast, such a correlation is not pointed out for the group II. As the value for xi t is not statistically different for groups II1 and II2 and is close to the normal value in both groups, the existence of a rheological protection against the retinopathy could be involved.(ABSTRACT TRUNCATED AT 250 WORDS)

[Role and modalities of insulin treatment in type 2 diabetics]. / Place et modalités de l'insulinothérapie chez le diabétique de type 2.

INTRODUCTION: The natural history of type 2 diabetes mellitus is characterized by an inescapable and gradual worsening of a decrease in insulin secretion. Thus after several years of progress, less than half of type 2 diabetic patients have good glycemic control. This explains the increase in insulin prescription to type 2 diabetic patients in France in recent years. This work's objective is to take into account recent publication data to clarify the status of and adjustments in insulin therapy. CURRENT KNOWLEDGE AND KEY POINTS: The benefit of insulin treatment-mediated glycemic control optimization on microvascular complications is now proven. However, there is still controversy concerning macrovascular complications. Hypoglycemic risk in type 2 diabetic patients is limited and the main problem with insulin treatment is weight gain. Following failure with treatment by tablets, the most suitable treatment in terms of metabolic improvement, weight gain limitation and treatment adhesion is to add an intermediate insulin injection at bedtime. The next step remains several injections a day, with metformine addition if possible. FUTURE PROSPECTS AND PROJECTS: Therapeutic treatment in type 2 diabetes mellitus may become an earlier start of insulin therapy to preserve the remaining pancreatic insulin reserve. The role of brief and long-lasting insulin analogues, as well as inhaled insulin, which will soon be available, should be specified.

[Intolerance to carbohydrates: the seven questions]. / Intolérance aux hydrates de carbone: les sept questions.

The borderline between diabetes and intolerance to carbohydrates has been drawn on the basis of prospective studies which determined a glycaemic threshold marking the risk for microangiopathy. On the other hand, the borderline between intolerance to carbohydrates and normal glucose tolerance remains arbitrary: 25% for subjects who are intolerant to carbohydrates return to normal glucose tolerance within 10 years. This is due to the fact that intolerance to carbohydrates is a heterogeneous entity which should be dismembered according to the severity of insulin deficiency and to the degree of insulin resistance. Alteration of insulin secretion is perhaps the most specific marker of susceptibility to non insulin dependent diabetes, but insulin resistance is certainly the principal factor exhausting insulin secretion and leading to non insulin dependent diabetes. Insulin resistance and the hyperinsulinism it creates seem to facilitate atherogenesis, even when glucose tolerance is still normal, so that the oral glucose tolerance test is not only poorly reproducible but loses a great deal of its value in the early detection of vascular risk. Measurements of fasting and post-prandial glucose levels and of A1C haemoglobin, cholesterol, triglyceride, and HDL cholesterol levels usually make it possible to classify subjects into one of the three following categories: (1) no risk of macro- or microangiopathy; (2) diabetes with a risk of macro- or microangiopathy; (3) intolerance to glucose with risk of atherogenesis but no risk of microangiopathy. The oral glucose tolerance test probably remains useful within a small set of values that are either very slightly above normal or dissociated. Measuring blood insulin levels might be a better way of assessing the risk of atherogenesis, but the clinical use of this test requires evaluation.

[Adrenal histoplasmosis in a non-insulin-dependent diabetic patient]. / Histoplasmose surrénalienne chez un sujet idabétique non insulinodépendant.

Adrenal histoplasmosis is a rare infection that can be misdiagnosed as tuberculosis. We present here a case of adrenal histoplasmosis in a 65 year-old male diabetic with marked weight loss. Laboratory investigations noticed an inflammatory syndrome and the abdominal computed tomography scanner reported an heterogenous left adrenal mass of 6 cm in diameter. Hormonal as well as bacteriological studies were negative. The patient was operated and the histopathological examination proved that the mass was a tuberculoma and an anti-tuberculous treatment was started. Four months later, the patient suffered from recurrence of symptoms and laboratory investigations confirmed the inflammatory syndrome and the abdominal computed tomography scanner showed a right adrenal mass. A surgical biopsy was performed and specific fungal researches proved that the lesion was due to Histoplasma capsulatum. The patient experienced a remarkable improvement under anti-fungal treatment.

[Innocuousness of the limited reuse of injection materials by insulin-dependent diabetics]. / Innocuité de la réutilisation limitée du matériel d'injection chez les diabétiques insulino-traités.

A survey was conducted in 120 insulin-dependent diabetics to determine their routine daily procedure for insulin injection and the possible reuse of the material employed. Aseptic precautions were usually sufficient, half of the diabetic patients (51.6%) conforming with the overall rules for hygiene generally recommended. Spontaneous reuse of injection material was rare (10/120), and local incidents as a result of reuse infrequent: pain from the 3rd injection in 2 patients and an abdominal abscess in a third case due to total lack of asepsis rules. Insulin injections in 37 insulin-dependent diabetics admitted to hospital care were administered throughout their stay by means of plastic syringes and needles used 3 times consecutively. The mean number of needles-syringes used per diabetic was 7.3, representing a total of 813 injections. Infectious sequelae were not observed and minor local incidents (pain, pruritus) were rare and unrelated to the reuse of equipment. Limited reuse, under satisfactory conditions of asepsis, of material termed for "once only use" appears to be free from risk particularly with respect to infection. Generalization of this practice will provide substantial economy in the treatment of diabetes.

[Role of the polyol pathway in the occurrence of degenerative complications of diabetes]. / Rôle de la voie des polyols dans la survenue des complications dégénératives du diabète.

The activity of the polyol pathway--a non insulin-dependent metabolic pathway of glucose--is increased in diabetic patients. Polyol accumulation is involved, by a myoinositol-dependent mechanism, in the pathogenesis of some degenerative complications of diabetes. Thus, sorbitol accumulation in the eye lens and in nerves seems to be an important factor in the development of cataract and in the slowing down of nerve conduction. Recent studies suggest that the polyol pathway may play a role in early structural abnormalities of retinal and renal microangiopathy. Synthetic aldose reductase inhibitors could be used for a physiopathogenic treatment of these complications, but the first trials in diabetic neuropathy proved disappointing. Further studies, prolonged and well controlled, are necessary to pronounce on the future of this new category of drugs.

[Heart involvement in diabetic patients]. / Les atteintes cardiaques du diabétique.

Diabetic cardiomyopathy appears to be due to "premature ageing" of the myocardium which loses some of its compliance and becomes less sensitive to catecholamines. The condition seems to be severe mainly in those frequent cases where it is associated with hypertensive and/or ischaemic cardiomyopathy. Neuropathic denervation of the heart, usually partial and predominantly affecting the parasympathetic system, might play a part in the myocardial dysfunction. It has been held responsible for sudden death, but its real consequences in diabetic patients remain to be assessed. Coronary artery disease is the most common cardiac complication of diabetes mellitus: it accounts for 50 per cent of deaths among noninsulin-dependent, and 25 per cent among insulin-dependent diabetic subjects. Its incidence does not seem to decline and its severity, notably in women, is demonstrated by a mortality rate that is twice as high as that observed in the non-diabetic population; hence the importance of primary prevention and treatment of risk factors. However, the specificity to abnormal lipid metabolism, notably hypertriglyceridaemia, the potentiation by chronic hyperglycaemia of the harmful effects of arterial hypertension, and the possible responsibility of coagulation disorders and hyperinsulinism are points that have not yet been elucidated. We still do not know whether the objectives to be attained in terms of plasma cholesterol, triglycerides and fibrinogen levels, as well as of blood pressure values, should be different in diabetic and non-diabetic subjects. In any case, the treatment of risk factors should be accompanied by a systematic search for silent ischaemia which is 2 to 3 times more frequent among diabetic patients. Detection of silent ischaemia by electrocardiography during exercise and/or Holter recordings, and by echocardiography and/or thallium scintigraphy should be performed not only in diabetic patients with coronary artery disease but also to those with other risk factors or albuminuria.

[Blood glucose and insulin secretion after meals rich in simple and complex carbohydrates, in non-insulin-dependent diabetics]. / Glycémies et insulino-sécrétion après des repas riches en sucres simples et complexes chez des diabétiques non insulino-dépendants.

In 10 well controlled non insulin-dependent diabetics, 25 g of complex sugars were replaced by the same amount of simple sugars in each of two isocaloric meals identical in their lipid, protein and carbohydrate contents. This had no detrimental effect on postprandial glycaemic and insulin responses. There were no statistically significant changes in areas under the curve and kinetics of glycaemic, insulin and peptide C responses after ingestion of limited amounts of simple sugars. It appears from these results that well controlled, non insulin-dependent diabetic patients without marked postprandial fluctuations in glycaemia (as confirmed by self-performed capillary blood tests) can be authorized to take 25 to 40 g of simple sugars (preferably fructose) during meals.

[Diabetic microangiopathy. Role of capillaroscopy]. / Microangiopathie diabétique. Place de la capillaroscopie.

In order to evaluate the significance of ungual and conjunctival microvascular abnormalities observed in diabetics prior to retinopathy, nailfold and conjunctival capillaroscopy was performed in 20 controls and 40 insulin-dependent diabetics of the same age. The diabetics were divided into 4 groups according to their state of retinopathy: absent, incipient, non-proliferative and proliferative. No difference was found between controls and diabetics and between groups of diabetics in the frequency of conjunctiva microaneurysms and specific nailfold microangiopathy, nor even in that of the so-called characteristic "fish shoal" image. The percentage of abnormalities detected was concordant with the results of previous studies in diabetics (12.5 per cent of non-specific organic microangiopathy), but it was 2 to 4 times higher than the frequency usually found in non-diabetic controls. This discrepancy could be due to the method used, since in contrast with earlier studies the operator did not know whether the subject was diabetic or not and was unaware of the patient's retina state. In the absence of other blind and prospective studies, capillaroscopic examination for diabetic microangiopathy should be reserved strictly to clinical research.

[Nocturnal hypoglycemia in insulin-dependent diabetics]. / Hypoglycémie nocturne du diabétique insulinodépendant.

OBJECTIVES: Repeated hypoglycaemia has been reported to impair recognition of subsequent hypoglycaemia with a high risk of severe hypoglycaemia. This intensified insulin therapy may be dangerous in insulin-dependent diabetes mellitus (IDDM) patients with unawareness of hypoglycaemia. METHODS: We assessed the incidence of nocturnal hypoglycaemia and the benefit of an additional bedtime snack in IDDM patients treated by 2 or 3 daily injections. Capillary blood glucose was measured by finger strip at 10 p.m. and plasma venous glycaemia was determined at 0, 2, 4 and 8 a.m. RESULTS: The study was composed of two phases. In the first phase, patients (n = 93) did not receive any snack at bedtime. Blood glucose fell to 2.75 mmol/l or less in 33%. Among the 40 patients with a 10 p.m. glycaemia of 9 mmol/l or less, 57.5% experienced nocturnal hypoglycaemia vs 15% of the 53 others. The second phase concerned 106 IDD patients. An additional bedtime snack was given when 10 p.m. blood glucose was 9 mmol/l or less. The incidence of hypoglycaemia fell to 32% (14 of 44 IDDM) i.e. a significant benefit of 44% (p < 0.01). However patients who received this additional bedtime snack had a slightly higher 8 a.m. glycaemia than those with 10 p.m. glycaemia at 9 mmol/l or less during the first phase (9.61 +/- 5.67 mmol/l vs 7.75 +/- 4.30 mmol/l) but this result is not significant. CONCLUSION: Prevention of nocturnal hypoglycaemia may be achieved in IDDM patients by bedtime glucose determination and an additional snack when glycaemia is 9 mmol/l or less.

[Surgical reduction of the external ligament for chronic instability of the tibio-tarsal joint. Apropos of 58 reviewed cases]. / Instabilité chronique de l'articulation tibio-tarsienne remise en tension ligamentaire externe. A propos de 58 cas revus.

Between 1975 and 1986, 75 cases of surgical tightening of the lateral ligament have been performed for chronic instability of the ankle. 58 of them have been reviewed with a mean delay of 36 months (extremes of 6 months to 6 years). Surgery corrected completely the instability four out of five times. In six patients there still remained more or less incapacitating pain. Talo-navicular movements were constantly preserved, as well as that of the sub-talar joint, except in six cases where it was slightly diminished. The results have been excellent in 18 cases; very good in 18 cases; good in 6 cases; mild in 8 cases and poor in 4 cases. Furthermore, four patients who originally had an excellent or very good results have subsequently presented with a recurrence of joint laxity and instability following a new severe ankle sprain. X-ray results were less satisfactory as the joint laxity was only partially controlled (average tilt of 7 degrees). But all joint laxities except one have been improved by this type of surgery. After failure of proprioceptive rehabilitation which must be performed systematically, surgical tightening of the lateral ligament can be proposed, and should be preferred to peroneus brevis ligamentoplasties, which are more traumatic and less physiological.

[Severe lesions of the petrous bone caused by pseudomonas aeruginosa]. / Lésions pétreuses graves dues au pseudomonas aeruginosa.

Pseudomonas aeruginosa is often isolated in infections of the ear cleft. In some circumstances, this organism can cause serious petrous or peri-petrous lesions. Two pictures are seen: Malignant external otitis with severe headaches, signs of external otitis, and usually pseudomonas aeruginosa is isolated. This is usually seen in an elderly diabetic patient. Nerve paralysis is the main risk. The other complications, very grave in the past, are rare nowadays with the use of selective antibiotic treatment. Pseudomonas aeruginosa is also the causative organism in extensive osteitis of the skull base. Diagnostic problems are seen in case of specific infections or tumoral lesions. The treatment includes the same medications as for the malignant external otitis, as well as complete surgical excision.

[Pituitary abscess. Study of a case and review of the literature]. / Abcès hypophysaire. Etude d'un cas et revue de la littérature.

The authors report one case of pituitary abscess; the diagnosis of which was particularly difficult due to its association to a multiple sclerosis that began twelve years before. A review of thirty-one pituitary abscess reported in the literature from 1970 to 1985 is made. Opto-chiasmatic compression is observed in fifty-five per cent of the cases, pituitary insufficiency in fifty-five per cent, and meningitis in sixty per cent of the cases. Although the characteristic association of meningitis and pituitary tumor symptoms occur in thirty per cent of the cases, the diagnosis is made at surgery. Pituitary adenoma and craniopharyngioma were the most frequent preoperative misdiagnosis for pituitary abscess. The extended use of cerebral C.T. Scan will allow an easier recognition of this rare entity. The discussion includes life and visual prognosis. The etiology remains unexplained in nearly half of the cases.