Practical implementation of automated closed-loop insulin delivery: A French position statement.

Automated closed-loop (CL) insulin therapy has come of age. This major technological advance is expected to significantly improve the quality of care for adults, adolescents and children with type 1 diabetes. To improve access to this innovation for both patients and healthcare professionals (HCPs), and to promote adherence to its requirements in terms of safety, regulations, ethics and practice, the French Diabetes Society (SFD) brought together a French Working Group of experts to discuss the current practical consensus. The result is the present statement describing the indications for CL therapy with emphasis on the idea that treatment expectations must be clearly defined in advance. Specifications for expert care centres in charge of initiating the treatment were also proposed. Great importance was also attached to the crucial place of high-quality training for patients and healthcare professionals. Long-term follow-up should collect not only metabolic and clinical results, but also indicators related to psychosocial and human factors. Overall, this national consensus statement aims to promote the introduction of marketed CL devices into standard clinical practice.

Continuous glucose profiles with vildagliptin versus sitagliptin in add-on to metformin: results from the randomized Optima study.

AIM: To compare continuous glucose monitoring (CGM) profiles on vildagliptin versus sitagliptin in addition to metformin, in patients with inadequately controlled type 2 diabetes mellitus (HbA(1c) 6.5-8.0%). METHODS: A multicenter, prospective, randomised, open-label study with blinded endpoint analysis. CGM data acquired over three days--firstly on metformin alone and then 8 weeks after the addition of either vildagliptin (n=14) or sitagliptin (n=16)--were blinded and analyzed centrally. RESULTS: In comparable populations with a mean baseline HbA1c of 7.1%, 24-hour glucose variability--measured by mean amplitude of glucose excursions and standard deviation of mean glucose concentration--showed similar improvement on both drugs versus metformin alone. In contrast, a series of predefined parameters reflecting daily glycaemic control--mean 24-hour blood glucose concentration, and the times spent in the optimal glycaemic range (70-140 mg/dL) and above the hyperglycaemic thresholds of 140 and 180 mg/dL together with the corresponding AUC values--were significantly improved from baseline only in the vildagliptin arm. In addition, overall hyperglycaemia (AUC[24 h] > 100 mg/dL) significantly dropped from baseline on vildagliptin [-37%] but not on sitagliptin [-9%], while postprandial hyperglycaemia (AUC[0-4 h] × 3) was significantly reduced on both, and basal hyperglycaemia (overall--postprandial hyperglycaemia was reduced only on vildagliptin [-41%; P = 0.04]). CONCLUSIONS: The addition of a DPP-4 inhibitor significantly reduced glycaemic variability with no difference between the two drugs. However, vildagliptin induced better circadian glycaemic control than sitagliptin with a significant decrease on overall hyperglycemia, mainly driven by reduction on basal hyperglycaemia.

Effects of a new prolactin inhibitor, CV 205-502, in the treatment of human macroprolactinomas.

The effects of a new PRL inhibitor, CV 205-502 (CV), on human macroprolactinomas were studied in nine patients according to a prospective protocol. Five patients had undergone surgery leaving tumor remnants and persistent hyperprolactinemia. The four others were de novo patients, two of whom had received short term treatment with Parlodel. Plasma PRL levels ranged from 235-6050 micrograms/L before treatment. The doses of CV used in this trial ranged from 0.075-0.600 mg. Plasma PRL normalized in eight of the nine patients during treatment with CV. The time to normalize varied from 2 weeks to 9 months, and the doses from 0.075-0.450 mg. A tumor volume reduction of more than 50% was obtained in all four patients who had not been operated on before CV treatment. Only one of the five patients with postoperative tumor remnants had no reduction in tumor size. The drug was generally well tolerated, and no patient interrupted the treatment. Slight and short-lasting gastrointestinal symptoms were noted in several patients, and a single episode of fainting occurred in one patient when the drug was not taken at bedtime as instructed. A noticeable and persistent weight loss with anorexia was noted in two patients. Since CV 205-502, administered in a single daily dose, has tolerable side-effects and is effective in reducing PRL secretion and tumor size, it can be considered to be a useful treatment for macroprolactinomas.

Plasma alpha-subunit levels during the treatment of pituitary adenomas with the somatostatin analog (SMS 201-995).

The effect os SMS 201-995 (Sandostatin), a long-acting somatostatin analog, on different types of pituitary adenomas including alpha-subunit elevation is illustrated in this report. Treatment induced a fall in hCG levels in a woman with a pituitary adenoma producing only alpha-subunit. In 3 acromegalic patients, there was only a partial drop in GH and alpha-hCG. The same effect was observed in a woman with menopausal FSH and LH levels. SMS reduced plasma TSH and alpha-hCG in a case of thyrotropic adenoma. Two patients exhibiting FSH- and alpha-hCG-secreting adenomas did not respond to acute administration of SMS 201-995. More patients have to be treated before a definitive statement can be made on the usefulness of somatostatin analogs in the management of different types of pituitary adenomas.

Insulin-mediated glucose disposal in type 1 (insulin-dependent) diabetic subjects treated by continuous subcutaneous or intraperitoneal insulin fusion.

In order to determine if intraperitoneal insulin infusion could improve the insulin resistance of type 1 diabetic patients we have used the englycaemic insulin clamp technique in order to study the effects of insulin on glucose disposal in four C peptide negative type 1 diabetic patients treated by continuous subcutaneous or intraperitoneal insulin infusion and in five control subjects. Compared to control subjects, the diabetic patients treated by subcutaneous insulin infusion had a decreased maximal capacity of glucose utilization (diabetics: 12.6 +/- 0.3 mg.kg-1.min-1; controls: 15.7 +/- 0.7 mg/kg-1.min-1, p less than 0.01) and a trend towards higher half-maximally effective insulin concentrations (diabetics: 70 +/- 11 mU/l-1, controls: 48 +/- 4 mU/l-1). Treatment of the diabetic patients by intraperitoneal insulin infusion for 2 months decreased their mean peripheral free insulin levels (during subcutaneous infusion: 23.5 +/- 2.2 mU/l-1; during intraperitoneal infusion: 18.4 +/- 1.4 mU/l-1, p less than 0.05). However, mean daily insulin requirements were not decreased (during subcutaneous infusion: 0.59 +/- 0.05 U/kg-1.day-1; during intraperitoneal infusion: 0.57 +/- 0.03 U/kg-1.min-1). Moreover, the diabetic patients had a consistently lower maximal capacity of glucose utilization (12.6 +/- 0.7 mg kg-1.min-1) than control subjects (p less than 0.01) without modification of the half-maximally effective insulin concentration (62 +/- 10 mU.l-1). In conclusion, the only benefit of intraperitoneal insulin infusion was a reduction of peripheral free insulin levels; this decrease of peripheral insulinaemia was not associated with an improvement in the insulin resistance of diabetic patients.

Lack of beta-adrenergic role for catecholamines in the development of hyperglycemia and ketonaemia following acute insulin withdrawal in type I diabetic patients.

In order to evaluate the role of beta-receptor mediated effects of catecholamines in the metabolic deterioration following insulin withdrawal in insulin-dependent diabetic patients we have measured in 5 patients metabolic substrate and hormone concentrations during a 6 hours arrest of insulin infusion, without or with a simultaneous infusion of propranolol. During insulin deprivation plasma epinephrine and norepinephrine increased slightly (from 107 +/- 10 ng/L to 173 +/- 6 ng/L and from 307 +/- 37 ng/L to 518 +/- 77/ng/L respectively (p less than 0.05), cortisol decreased physiologically, but growth hormone and glucagon were not significantly modified. Free insulin decreased progressively from 12.2 +/- 2.5 mU/L to 5.4 +/- 1.1 mU/L (p less than 0.01). Blood glucose and ketone bodies rose sharply before any significant change in catecholamine levels. Plasma free fatty acids and blood glycerol increased progressively and their rise appeared somewhat temporally related to the variations of catecholamine levels. The addition of propranolol to insulin deprivation did not modify the changes in hormone concentrations in spite of a slightly greater rise of epinephrine (from 78 +/- 4 ng/L to 179 +/- 7 ng/L, p less than 0.05) and norepinephrine (from 395 +/- 80 ng/L to 679 +/- 153 ng/L, p less than 0.05). The rises of glucose and ketone bodies were unaffected whereas the increases of free fatty acids and glycerol were slightly blunted. In conclusion, we have no evidence for a beta-adrenergic mediated role for catecholamines in the development of hyperglycaemia and ketonaemia in non-stressed insulin deprived diabetic patients, and only small evidence for a permissive effect on lipolysis.

Glucose metabolism in experimental hyperthyroidism: intact in vivo sensitivity to insulin with abnormal binding and increased glucose turnover.

The characteristics of the dose response of insulin on the glucose turnover rate and erythrocyte insulin binding parameters were determined in five normal men before and during experimentally induced hyperthyroidism [L-T4 (2 micrograms kg-1 day-1) for 4 weeks with additional L-T3 (1 microgram kg-1 day-1) for the following 3 weeks]. Hyperthyroidism was characterized by significant rises in T3 from 1.92 +/- 0.17 (+/- SEM) to 3.66 +/- 0.17 nmol/liter (P less than 0.01) and resting metabolic rate from 39 +/- 0.7 to 48 +/- 1 watt/m2 (P less than 0.001). While the subjects received a diet adapted to the metabolic rate, blood glucose rose from 3.8 +/- 0.07 to 4.46 +/- 0.11 mmol/liter (P less than 0.05) without a significant change in plasma insulin. During the insulin dose-response study, glucose infusion rates were unaltered by hyperthyroidism, and neither the maximum effect nor the sensitivity to insulin was altered. Glucose turnover rate, measured using [6,6-2H2]glucose as tracer, was determined in the basal state and during the 0.4 mU kg-1 min-1 insulin infusion. In the basal state, it was significantly increased by hyperthyroidism (control, 2.3 +/- 0.1; hyperthyroidism, 3.7 +/- 0.1 mg kg-1 min-1). During the insulin infusion, hepatic glucose production was totally suppressed before T4 and T3 treatment, but was 0.96 +/- 0.39 mg kg-1 min-1 during T4 and T3 treatment. A marked decrease in the insulin binding affinity to erythrocytes was found without a change in the insulin receptor number. In conclusion, glucose metabolism in experimental hyperthyroidism is characterized by 1) increases in basal glucose production and utilization; 2) antagonism between the effect of insulin and hyperthyroidism at the hepatic level; and 3) lack of peripheral insulin resistance in spite of marked alteration in erythrocyte insulin binding affinity.

beta 2- and alpha 2-adrenergic receptors and receptor coupling to adenylate cyclase in human mononuclear leukocytes and platelets in relation to physiological variations of sex steroids.

In view of evidence, largely in animals, indicating effects of sex steroids on adrenergic receptors, we measured mononuclear leukocyte (MNL) beta 2-adrenergic receptors and adenylate cyclase sensitivity to stimulation by isoproterenol as well as platelet alpha 2-adrenergic receptors and sensitivity of sodium fluoride-stimulated adenylate cyclase to inhibition by epinephrine in 3 groups of normal humans with physiologically disparate levels of testosterone, estradiol, and progesterone (10 normal men and 10 normal women, the latter sampled in both the follicular and luteal phases of their menstrual cycles). Differences in testosterone, estradiol, and progesterone were as expected; testosterone levels were 10-fold higher in men, and progesterone levels were 20-fold higher in luteal phase women. T4, cortisol , and norepinephrine levels did not differ. Basal plasma epinephrine concentrations were slightly but significantly higher in luteal phase women [34 +/- 5 (+/-SE) pg/ml] than in follicular phase women (16 +/- 3 pg/ml; P less than 0.01) or men (20 +/- 3 pg/ml; P less than 0.05). There were no significant differences among these 3 groups in the densities or affinities of MNL beta 2-adrenergic or platelet alpha 2-adrenergic receptors or in the corresponding MNL and platelet adenylate cyclase sensitivities. Thus, there is not a generalized effect of physiological variations of testosterone, estradiol, and progesterone on adrenergic receptors or adenylate cyclase. To the extent that the adrenergic receptors and adenylate cyclase activities of circulating cells reflect those of extravascular catecholamine target cells, these data provide no support for a role of physiological variations of testosterone, estradiol, or progesterone in the regulation of catecholamine action in humans.

Role of catecholamines in the ketonemic response to somatostatin in normal man.

In order to determine if a rise of circulating catecholamines occurs during somatostatin (SRIF) infusion in normal man, and if this increase plays a significant metabolic role, we infused four normal subjects with SRIF (500 micrograms/h) alone or associated with either alpha-(phentolamine) or beta-(propranolol) adrenergic blocking agents. During SRIF infusion, the initial small decrease in blood glucose was followed by a rise of epinephrine from 25-46 ng/liter (range) to 117-143 ng/liter (range) (P less than 0.05) at 80 min and norepinephrine from 204 +/- 16 to 418 +/- 60 ng/liter at 90 min (P less than 0.05). Thereafter, plasma nonesterified fatty acids, blood glycerol, and ketone bodies increased significantly. Phentolamine adjunction modified neither the catecholamines rise, nor the metabolic changes. Propranolol adjunction did not modify the glucose fall and the catecholamine rise, but resulted in blunted increments of fatty acids and glycerol and in an almost complete suppression of the increase of ketone bodies. These results suggest that the enhanced lipolysis and ketogenesis observed during SRIF infusion are not only due to the SRIF-induced insulin deficiency but also in part to a beta-receptor mediated effect of catecholamines.

Mononuclear leukocyte beta 2-adrenergic receptors and adenylate cyclase sensitivity in insulin-dependent diabetes mellitus.

Patients with insulin-dependent diabetes mellitus (IDDM) have been found to have a heightened hyperglycemic response to epinephrine. To determine if patients with IDDM have increased sensitivity of cellular beta 2-adrenergic receptor-effector systems, we assessed beta 2-adrenergic receptors and adenylate cyclase sensitivities to isoproterenol in partially purified mononuclear leukocyte (MNL) plasma membranes from 10 patients with IDDM (without adrenergic neuropathy) and 10 matched nondiabetic controls. MNL beta 2-adrenergic receptor densities (Bmax = 48 +/- 8 fmol [3H] DHA/mg protein in IDDM, 44 +/- 3 fmol [3H] DHA/mg protein in controls) and binding affinities (apparent KD = 0.3 +/- 0.07 nM in IDDM, 0.3 +/- 0.04 nM in controls) did not differ. Further, MNL adenylate cyclase activities were not significantly different either at baseline (325 +/- 86 pmol/mg protein/15 min in IDDM, 275 +/- 49 pmol/mg protein/15 min in controls) or in response to isoproterenol (842 +/- 229 pmol/mg protein/15 min in IDDM, 608 +/- 86 pmol/mg protein/15 min in controls). Thus, the data do not support the presence of a generalized alteration of beta-adrenergic receptors or adenylate cyclase sensitivity in IDDM. To the extent that MNL beta 2-adrenergic receptors and adenylate cyclase activities reflect those of extravascular catecholamine target cells, these findings suggest that the heightened hyperglycemic response to epinephrine exhibited by patients with IDDM is not due to increased sensitivity of cellular beta 2-adrenergic receptor-effector systems and is best attributed to the altered hormonal milieu of the insulin-deficient state.

Glucuronide and sulfate catecholamine conjugates in rat and human plasma.

We have developed a method to selectively estimate free, glucuronidated and sulfated catecholamines (epinephrine [E], norepinephrine [NE], dopamine [DA]) in a single plasma sample. The method incorporates the first step of the catecholamine radioenzymatic assay and the selective enzymatic hydrolysis of conjugates by glucuronidase or sulfatase preparations. The method has been applied to rat and human plasma with a view to determine the relative importance of either conjugate (sulfate or glucuronide) toward free catecholamines. No previous reports were available for the concentration of either conjugate in rat plasma or the level of glucuronide conjugate in human plasma. Both sulfate and glucuronide conjugate of the three catecholamines were found in rat and human plasma, at different levels. Sulfate conjugates predominated in man and glucuronides in rat. In human, hand immersion in ice water for three minutes, which increased free catecholamine levels in the first minutes of the test, elicited too a delayed increase of glucuronide levels at the 30th minute (except for DA glucuronide which was already elevated at the third minute). As to the sulfates, only E sulfate was increased at the 10th minute. Our results suggest that glucuronidation may be an important pathway for catecholamine metabolism in man at rest or under sympathetic stimulation. In rat, our data point out the influence of blood sampling conditions (dietary, catheterization, decapitation) on the studied compounds and suggest that the nearest conditions from basal state may be fulfilled in sucrose-fed catheterized rats. The predominance of glucuronides in rat plasma agrees with previous metabolic reports.