Glucose control during a driving training in patients with type 1 and type 2 diabetes mellitus - a randomised, controlled trial.

AIM: To investigate the effect of prolonged acute mental stress by means of a driving training on glucose control in patients with type 1 and type 2 diabetes mellitus. METHODS: 39 patients with insulin-treated diabetes (18 type 1, 21 type 2 diabetes) were exposed to mental stress by means of a 2 h-driving training. The training session started 15 min after intake of a standard meal. Blood glucose, blood pressure, heart rate, salivary cortisol, and subjective stress perception were monitored in regular intervals and compared to a control day. RESULTS: On the stress testing day, blood pressure rose from 142/86±16/9 mmHg to 162/95±22/11 mmHg (p<0.001), heart rate from 72±11 bpm to 86±16 bpm (p<0.001) and subjective stress perception from 1.4±0.6 to 4.7±2.5 points (p<0.001). Salivary cortisol concentrations increased from a median of 5.1 nmol/l (Interquartile Range (IQR) 3.5-7.5 nmol/l) at baseline to 7.7 nmol/l (IQR 4.7-12.8 nmol/l, p<0.001), all these measurements remained stable on the control day. Glucose control showed no significant difference on the stress testing day compared to the control day (mean difference over time=0.22 mmol/l, 95%-CI -1.5 to +1.9 mmol/l, p=0.794). A multivariate linear regression and correlation analysis showed no association of demographic characteristics (diabetes type, age, body mass index (BMI), diabetes duration, HbA1c), objective or subjective stress parameters with the course of glucose concentrations during the driving training. CONCLUSIONS: Although a 2 h-driving training causes increased subjective and objective stress parameters, glucose control is maintained in patients with insulin-treated diabetes.

Monitoring for potential residual disease activity by serum insulin-like growth factor 1 and soluble Klotho in patients with acromegaly after pituitary surgery: is there an impact of the genomic deletion of exon 3 in the growth hormone receptor (d3-GHR) gene on "safe" GH cut-off values?

BACKGROUND: Acromegaly is an illness usually defined by excessively high growth hormone (GH) and insulin like growth factor 1 (IGF-1) levels, the latter mainly reflecting GH action on the liver. IGF-1, also known as somatomedin C, mediates several actions of GH. The diagnosis and management of acromegaly is relatively straight forward, but long-term follow-up of patients can be difficult, as elevated IGF-1 levels can occur in the presence of apparently normalised GH levels and late recurrence of acromegaly may arise despite previous suppression on oral glucose tolerance testing. Data suggest this applies especially to patients in whom the GH receptor lacks exon 3. In such patients, GH may not always be a useful marker of disease, and traditional GH cut-offs may be misleading. Recent data suggest that soluble Klotho (sKlotho), besides and in addition to IGF-1, may help monitor the activity of GH-producing adenomas (presumably reflecting GH action on the kidneys) and may be a useful supplementary tool. METHODS: GHR genotyping was performed in 112 patients with acromegaly. IGF-1 and sKlotho levels were measured in the sera of patients before and after transsphenoidal surgery, with emphasis on patients judged inconclusively cured by surgery or with small residual tumour masses shortly after surgery. Patients were assessed for recurrence of acromegaly with GH levels (random or nadir during an oGTT). RESULTS: Of the 48 patients who underwent surgery between 2000 and 2009 and who had well-documented longer term follow-up at our institution, 29 had no biochemical evidence of residual disease activity after transsphenoidal surgery (marked reduction in IGF-1 and sKlotho levels, GH suppressible to <1 ng/ml) and were classified as in remission. 2 of these patients developed recurrent symptoms of acromegaly during follow-up with increasing levels of IGF-1 and sKlotho, and both patients were carriers of the d3-GHR genotype. CONCLUSIONS: Acromegalic patients with the d3-GHR polymorphism might be - for a given low postsurgical GH level - at higher risk for recurrence and may require a lower GH nadir during oGTT to be classified as in remission. Soluble Klotho could be useful in the follow-up of acromegalic patients. The question arises whether sKlotho not only reflects the activity of GH-secreting pituitary adenomas but whether Klotho (ectodomain clipping?) could also mediate selected actions of GH.

Excessively high soluble Klotho in patients with acromegaly.

OBJECTIVES: Klotho-deficient mice develop a syndrome resembling accelerated ageing, and genetic variants of Klotho have been associated with human ageing. In humans, serum levels of soluble Klotho decrease with age and with chronic renal failure. The aim of our study was to examine the relationship between excess growth hormone (GH) and serum levels of Klotho in patients with acromegaly, a disease usually caused by a pituitary adenoma, which is associated with high phosphate levels and reduced life expectancy. PATIENTS AND DESIGN: We determined the levels of soluble Klotho, GH and insulin-like growth factor 1 (IGF-1) in serum samples from 24 consecutive patients with acromegaly (nine women/15 men, age 28-76 years) before and after transsphenoidal surgery. RESULTS: Soluble Klotho levels were excessively high at baseline (mean ± SEM, 4.2 ± 0.7 ng mL(-1) ) and correlated with GH (r = 0.64), IGF-1 (r = 0.57) and tumour size (r = 0.5). In multiple regression analysis, soluble Klotho was associated with GH after correction for age, gender and levels of creatinine and phosphate (P = 0.029). After surgery, GH and IGF-1 levels decreased in all patients (from 26.3 ± 5.2 to 2.6 ± 0.6 µg L(-1) , P <0.0001, and from 588 ± 35 to 193 ± 12 µg L(-1) , P < 0.001, 0.0001, respectively). Creatinine increased from 71 ± 3 to 80 ± 3 µmol L(-1) (P < 0.001), and phosphate decreased from 1.37 ± 0.04 to 1.06 ± 0.02 mmol L(-1) (P < 0.001). The markedly increased preoperative levels of soluble Klotho returned towards normal after surgery (0.7 ± 0.1 ng mL(-1) , P < 0.0001). CONCLUSIONS: This is the first study to show dramatically increased soluble Klotho levels in an acquired disease in humans. Reversal following tumour removal suggests a causal relation between the GH-producing adenoma and high serum Klotho concentration in acromegaly.

Effect of psychological stress on glucose control in patients with Type 2 diabetes.

AIM: To investigate the effect of acute psychological stress on glucose concentrations in patients with Type 2 diabetes, in the fasting state as well as in the postprandial state. METHODS: Thirty patients (12 female) with Type 2 diabetes were included. Mean ± SD age was 60 ± 12 years, BMI 28.8 ± 4.2 kg/m(2), diabetes duration 8.9 ± 6.7 years and HbA(1c) 51 ± 9 mmol/mol (6.8 ± 0.8%). Using a non-randomized approach, all participants were exposed to moderate psychological stress by means of the Trier Social Stress Test: 10 participants in the fasting state and 20 participants 75 min after intake of a standard meal. Blood pressure, heart rate and salivary cortisol were monitored on the control day and the stress-test day. Glucose concentrations were assessed using a continuous glucose monitoring system. RESULTS: On the stress-test day, blood pressure rose from 117/73 ± 13/12 to 155/92 ± 22/14 mmHg, heart rate from 77 ± 11 to 91 ± 25 b min(-1) and salivary cortisol concentrations from 8.5 ± 3.7 to 26.4 ± 12.1 nmol/l (P < 0.001); these measurements remained unchanged on the control day. On the stress-test day, when the Trier Social Stress Test was applied 75 min after the intake of a standard meal, the glucose concentrations were significantly higher compared with the control day (mean difference 1.5 mmol/l, 95% CI 0.5-2.4, P = 0.003). In the fasting state, glucose concentrations slightly decreased during the control day but remained stable on the stress-test day (mean difference compared with the control day 0.7 mmol/l, 95% CI -0.7 to 2.0, P = 0.31). CONCLUSIONS: When stress is experienced in the postprandial period, acute psychological stress significantly increases glucose concentrations in patients with Type 2 diabetes.

Skipping meals or carbohydrate-free meals in order to determine Basal insulin requirements in subjects with type 1 diabetes mellitus?

INTRODUCTION: Basal insulin dose requirements in patients with type 1 diabetes may be derived from the course of glucose concentrations in the fasting state; i. e. by skipping meals. The present study examined whether fasting tests could be replaced by carbohydrate-free meals. MATERIAL AND METHODS: 16 adult patients with type 1 diabetes (10 male) on intensive insulin therapy participated in this prospective intervention study. Mean age (+/-SD) was 44+/-12 years, BMI 24+/-3 kg/m (2), mean HbA1c was 7.5+/-0.6% and duration of diabetes 15+/-12 years. All participants skipped dinner and plasma glucose concentrations were hourly monitored from 7 p.m. to 11 p.m. This blood glucose profile was compared with three test meals given at 7 p.m. at day 2-4, consumed either in the hospital (meal 1) or at home (meal 2 and 3). No insulin injection (except to basal insulin) was allowed. Test meals consisted of 2.5 g carbohydrate, 32.4 g protein, 52.0 g fat (according to 612 kcal). RESULTS: During 16 fasting tests plasma glucose concentration remained stable between 7.2+/-2.4 mmol/l at 7 p.m. and 6.8+/-2.8 mmol/l at 11 p.m. (p=0.461). Following the intake of near carbohydrate-free meals (48 tests), plasma glucose concentrations rose within 4 h from 6.7+/-2.0 at 7 p.m. to 9.8+/-3.4 mmol/l at 11 p.m. (p<0.0001). The increase in plasma glucose concentrations was similar in all three different meals tested. CONCLUSION: Plasma glucose concentrations significantly increase in patients with type 1 diabetes following the intake of carbohydrate-free meals. Carbohydrate-free meal-tests cannot replace skipping meal tests to determine the basal insulin requirement in patients with type 1 diabetes.

Omitting breakfast and lunch after injection of different long-acting insulin preparations at bedtime: a prospective study in patients with type 2 diabetes.

AIMS/HYPOTHESIS: The aim of this prospective trial was to compare the effect of different long-acting insulin preparations injected at bedtime on glucose concentrations in patients with type 2 diabetes omitting breakfast and lunch the next day. METHODS: Twenty patients (ten women) with type 2 diabetes who were on an intensified insulin therapy participated. Mean (+/-SD) age was 63 +/- 10 years, diabetes duration 18 +/- 9 years, BMI 32.5 +/- 5 kg/m(2), and HbA(1c) 7.3 +/- 0.7%. Patients received neutral protamine Hagedorn (NPH) insulin, insulin detemir or insulin glargine for at least 2 months; doses were adjusted to achieve morning blood glucose levels of <7 mmol/l. At the end of the respective treatment period, the long-acting insulin was injected at bedtime (at 22:45 hours) as usual but patients refrained from breakfast and lunch the next day; glucose was measured by a continuous glucose monitoring system (CGMS). RESULTS: Comparable glucose target ranges were reached at midnight (5.8 to 6.1 mmol/l) and at 07:00 hours (6.7 to 6.9 mmol/l) with all three insulin preparations, using mean doses of 29 +/- 10 U (NPH insulin), 33 +/- 13 U (insulin detemir), and 32 +/- 12 U (insulin glargine). Glucose levels between midnight and 07:00 hours were not significantly different for the three insulin preparations. Symptomatic hypoglycaemia did not occur from 08:00 to 16:00 hours; glucose concentrations during this time were slightly lower with NPH insulin than with insulin detemir (p = 0.012) and insulin glargine (p = 0.049). CONCLUSIONS/INTERPRETATION: Following bedtime injection of NPH insulin or of the analogues insulin detemir or insulin glargine, fasting glucose <7 mmol/l was achieved in the morning, without subsequent hypoglycaemia when participants continued to fast during the day.

TNF-alpha -308G>A polymorphism modulates cytokine serum concentrations and macrovascular complications in diabetic patients on aspirin.

BACKGROUND: Tumor necrosis factor (TNF)-alpha has pleiotropic effects in cytokine-mediated inflammation underlying atherogenesis. Activation of this inflammatory process is assumed to be different in diabetic and non-diabetic individuals. Previous studies in non-diabetic subjects showed no association between TNF-alpha -308G>A polymorphism and coronary artery disease. METHODS: Vascular complications and cytokine serum concentrations were assessed as a function of the TNF-alpha -308G>A polymorphism in 76 diabetic patients on low-dose aspirin. RESULTS: Of 76 adult diabetic patients, 18 (24%) carried the TNF-alpha -308A allele (17 AG, 1 AA) and 58 (76%) carried wild-type alleles (GG). Prevalence of macrovascular complications was 33% in TNF-alpha -308A allele carriers (AG+AA) and 78% in wild-type allele carriers (GG) (p<0.001). In contrast, prevalence of microvascular complications was 78% and 84%, respectively, and did not significantly differ between the study groups. TNF-alpha -308A allele carriers (AG+AA) compared to wild-type allele carriers (GG) had significantly lower median serum concentrations of hs-C-reactive protein (1.5 vs 2.9 mg/L, p=0.030), interleukin 1-beta (0.9 vs 1.2 ng/L, p=0.046), and interleukin-6 (3.6 vs 4.9 ng/L, p=0.023). In multiple regression analysis, the prevalence of macrovascular diabetic complications was significantly associated with TNF-alpha -308G>A polymorphism (p<0.001) and serum concentrations of HDL-cholesterol (p=0.007) while confounding effects of further variables were excluded. CONCLUSION: TNF-alpha -308G>A polymorphism modulates cytokine serum concentrations and macrovascular complications in diabetic patients on aspirin. Diabetic carriers of the TNF-alpha -308A allele might benefit more from a prophylaxis with low dose aspirin than non-carriers.

Assessment of basal insulin requirement using fasting tests in insulin-treated patients with type 2 diabetes mellitus.

AIMS: Characterizing the time course of the rise of blood glucose concentrations in the fasting state during the day and night in patients with type 2 diabetes. METHODS: 40 consecutive insulin-treated patients with type 2 diabetes underwent fasting tests on two different days with either no breakfast and lunch (fasting time of 20 hours) or no dinner (fasting time of 21 hours). Glucose-lowering medication was stopped prior to the test according to the half-life of the medication prescribed. At the start of the fasting tests, blood glucose concentrations were lowered to below 7 mmol/L using an insulin infusion. RESULTS: 26 men and 14 women were included in the study. Mean (+/-SD) age was 61+/-10 years, BMI 31+/-7 kg/m (2), and HbA1c 7.5+/-1%. Diabetes duration was 14+/-8 years and duration of insulin therapy had been prescribed for a mean of 6+/-6 years. During the daytime fast, plasma glucose concentrations rose by a mean of 0.8+/-1.6 mmol/L. During the nighttime fast, plasma glucose concentrations increased particularly after midnight, by 4.3+/-2.1 mmol/L, i.e. significantly more than during the daytime fast. CONCLUSIONS: Fasting blood glucose concentrations in the majority of insulin-treated patients with type 2 diabetes increase markedly after midnight. No similar increase is observed during the day. Thus, for most patients with type 2 diabetes, an intermediate- or long-acting insulin injected at bedtime with a peak action six to eight hours after injection should be appropriate.

Hypoglycemia in response to glucose and glucagon in insulinoma patients with a negative prolonged fast: functional and morphological properties.

A negative 72-h fast is usually considered to preclude the diagnosis of insulinoma. The aim of this study was to describe the functional and morphological properties of two exceptional patients with an insulinoma who had exhibited pre-operatively a negative 72-h fast. Despite the ability of tumor cells to turn off insulin secretion in response to low plasma glucose during 72 h of fasting, hyperinsulinemic hypoglycemia occurred in both patients in response to stimulation by classical secretagogues. Pre-operatively, both patients underwent oral and iv glucose challenge tests and iv glucagon stimulation test. Insulin secretion was rapidly stimulated by these secretagogues to an exaggerated extent and thereby caused hypoglycemia due to an insulin mass effect. In contrast to the common functional features during suppression and stimulation tests, the tumors differed widely with regard to insulin and proinsulin response to calcium during ASVS tests and morphological properties. In patient 1, the immunohistochemical proinsulin distribution pattern resembled that of normal beta-cells, i.e. the staining was restricted to the perinuclear area; insulin and proinsulin were not stimulated by calcium during the ASVS test. In patient 2, the proinsulin staining pattern was abnormal, i.e. proinsulin was also found in the periphery of tumor cells; insulin and proinsulin were stimulated by calcium. We conclude that normal or exaggerated rather than defective glucose sensing may explain hypoglycemia in these exceptional insulinoma patients. Different functional characteristics of these tumors can be correlated with distinct morphological properties.

Extensive spherical amyloid deposition presenting as a pituitary tumor.

A 71-yr-old man was admitted for further evaluation and trans-sphenoidal surgery of a pituitary tumor. He complained of impotence and decreased libido over a period of about 40 yr. Thirty-eight yr ago he was treated for bilateral gynecomastia with galactorrhea. Endocrinological investigation at presentation revealed only mild hyperprolactinemia and hypogonadotropic hypogonadism. Pituitary magnetic resonance imaging (MRI) showed a tumor up to 2.5 cm in diameter with infiltration of the sphenoid sinus and right cavernous sinus. The tumor exhibited a heterogeneous hyperintense signal on T1-weighted images and hypointense signal on T2-weighted images. Standard trans-sphenoidal surgery was performed and a brownish mass was found inside the sella, which was removed. Histological examination of the mass revealed extensive spherical amyloid deposits with strongly positive immunohistochemical staining for prolactin. Therefore, a prolactinoma with extensive spherical amyloid deposition was diagnosed. Extensive spherical amyloid deposition is a rare finding in prolactin-secreting pituitary adenomas. So far, characteristic radiological findings by MRI have been described only twice. Due to characteristic MRI findings, the diagnosis of extensive intrasellar amyloid deposition can be entertained pre-operatively. Trans-sphenoidal surgical resection is essential to confirm the diagnosis histologically and because of the potential lack of tumor shrinkage under dopaminagonist therapy in this type of prolactinoma.

A plasma glucose concentration below 2.5 mmol L-1 is not an appropriate criterion to end the 72-h fast.

CONTEXT: The classical end-point to terminate the 72-h fast in a patient evaluated for a hypoglycaemic disorder is the occurrence of hypoglycaemic symptoms in association with a low plasma glucose level. However, neither the symptoms nor the plasma glucose level have been exactly defined. OBJECTIVE: To determine whether a useful cut-off plasma glucose concentration as criterion to end the prolonged fast in the absence of neuroglycopenic symptoms can be defined. DESIGN: Single centre case-control study. SETTING: Tertiary referral hospital in Switzerland. SUBJECTS: The 72-h fast was prospectively performed in 23 consecutive patients (17 women and six men) following a standardized protocol between July 1999 and January 2002. All patients were referred to our clinic for evaluation of suspected hypoglycaemia. The criterion to end the fast before 72 h was defined by the occurrence of symptoms or signs typical for neuroglycopenia irrespective of plasma glucose levels. MAIN OUTCOME MEASURE: Insulin levels and insulin to plasma glucose ratios in insulinoma patients and in individuals without insulin-secreting tumours at termination of the fast and at plasma glucose levels

[General insulin therapy practice in type 2 diabetes mellitus]. / Praxis der Insulintherapie beim Diabetes mellitus Typ 2.

In most patients with Type 2 Diabetes, the primary treatment goal is near-normoglycemia. If diet, physical activity, and oral hypoglycemic agents fail to achieve the individual treatment goal, insulin therapy must be considered. Insulin therapy in patients with Type 2 Diabetes is safe, highly efficient and should be initiated not too late. We recommend to perform the insulin therapy in Type 2 Diabetics individually upon the patients characteristics, no general recommendation can be given. Possible approaches to start an insulin therapy in general practice are discussed. Insulin therapy may be initiated as bedtime insulin (depot insulin at bedtime) in combination with oral agents. In patients who fail to achieve good glycemic control with this combination therapy, mealtime insulin (short-acting insulin before the meals) may be introduced instead of the oral agents (multiple injection regimen). Bedtime insulin may be discontinued when fasting glucose concentrations remain in the desired range and no rise of glucose concentrations occurs during the night. The two-insulin-injection regimen with mixed insulin formulations may be initiated in patients with Type 2 Diabetes when a multiple injection regimen is not feasible. The two-insulin-injection should not be considered as the primary insulin strategy in patients with Type 2 Diabetes.

Coincidence of Behçet's disease and SAPHO syndrome.

A young woman presented with deteriorated visual acuity due to acute retinal vasculitis. The diagnosis of Behçet's disease was made on the basis of the ophthalmologic findings and recurrent oral and genital aphthous ulcerations. In the past, this young woman had been operated on several times because of progressive aseptic osteitis of the right clavicle. The actual examination revealed chronic osteitis, osteosclerosis and hyperostosis of the anterior chest wall, as well as severe acne papulopustulosa et conglobata. These findings resulted in an additional diagnosis of SAPHO syndrome. This report is the first description of Behçet's disease occurring in association with SAPHO syndrome, both fulfilling the diagnostic criteria.

[Hyper- and hypothyroidism: which tests are reliable in general practice?]. / Hyper- und Hypothyreose: Welche Tests sind in der Praxis sinnvoll?

Thyroid function is evaluated by measuring the serum concentrations of thyroid stimulating hormone (TSH) and free thyroxine (fT4). To confirm a normal thyroid function, a TSH within the normal range is usually sufficient. If hyperthyroidism or hypothyroidism is suspected clinically, the assessment of TSH in association with fT4 is recommended. Additional tests in the evaluation of hyper- and hypothyroidism should be performed depending on the clinically suspected diagnosis. Acquired primary hypothyroidism in the adult can be diagnosed by measurement of TSH and fT4. Additional investigations are usually unnecessary. The indications to perform a thyroid radionuclide scan, thyroid ultrasonography and the determination of thyroid antibodies in patients with primary hyperthyroidism are discussed.

Carcinoid syndrome, acromegaly, and hypoglycemia due to an insulin-secreting neuroendocrine tumor of the liver.

We report a patient with a hepatic neuroendocrine tumor showing an extraordinary change of the tumor's humoral manifestations from a clinically documented extrapituitary acromegaly and a typical carcinoid syndrome toward a hyperinsulinemic hypoglycemia syndrome. At the primary manifestation of the tumor, an increased serum level of insulin-like growth factor I due to overproduction of GHRH and an increased urinary excretion of 5-hydroxyindoleacetic acid were found. The clinical manifestation of the GHRH excess was an arthralgia, which resolved completely after operative tumor debulking and normalization of insulin-like growth factor I and GHRH serum levels. The secretion of serotonin from the tumor resulted in a typical carcinoid syndrome including right-sided valvular heart disease. On the later course of the disease, the humoral manifestations of the tumor were supplemented by the secretion of insulin, leading to recurrent severe hyperinsulinemic hypoglycemia. The hepatic origin of hyperinsulinism was demonstrated by selective arterial calcium stimulation. Moreover, tumor cells revealed insulin and C-peptide immunoreactivity in the immunohistochemical analysis. The patient died 8 yr after the initial diagnosis of the tumor, and a carefully performed autopsy procedure confirmed the absence of any extrahepatic tumor manifestation.