Glycaemic control without weight gain in insulin requiring type 2 diabetes: 1-year results of the GAME regimen.

INTRODUCTION: Weight gain appears to be unavoidable in patients with type 2 diabetes who are switched from oral agents to insulin therapy. Peripheral hyperinsulinism induced by the use of long-acting insulin may be the key to explain this adverse effect. AIM: The aim of this study was to investigate whether a regimen free of long-acting insulin can provide long-term glycaemic control without causing weight gain. PATIENTS AND METHODS: This is an uncontrolled, 1-year study comprising 58 patients with type 2 diabetes and secondary failure, age 30-75 years, BMI 25-35 kg/m(2), HbA1c > 7.5% and fasting C-peptide level > 0.3 mmol/l. All patients were treated with the GAME regimen, a combination of glimepiride administered at 20:00 hours for nocturnal glycaemic control, insulin aspart three times daily for meal-related glucose control and metformin. RESULTS: Seventy-one per cent of the patients were considered evaluable. HbA1c decreased from 10.0 +/- 0.3 to 7.4 +/- 0.1% (p < 0.001). Fifty-nine per cent reached HbA1c levels

Letrozole normalizes serum testosterone in severely obese men with hypogonadotropic hypogonadism.

BACKGROUND: Morbid obesity is associated with increased estradiol production as a result of aromatase-dependent conversion of testosterone to estradiol. The elevated serum estradiol levels may inhibit pituitary LH secretion to such extent that hypogonadotropic hypogonadism can result. Normalization of the disturbed estradiol-testosterone balance may be beneficial to reverse the adverse effects of hypogonadism. AIM: To examine whether aromatase inhibition with Letrozole can normalize serum testosterone levels in severely obese men with hypogonadotropic hypogonadism. PATIENTS AND METHODS: Ten severely obese men, mean age 48.2 +/- 2.3 (s.e.) years and body mass index 42.1 +/- 2.6 kg/m(2), were treated with Letrozole for 6 weeks in doses ranging from 7.5 to 17.5 mg per week. RESULTS: Six weeks of treatment decreased serum estradiol from 120 +/- 20 to 70 +/- 9 pmol/l (p = 0.006). None of the subjects developed an estradiol level of less than 40 pmol/l. LH increased from 4.5 +/- 0.8 to 14.8 +/- 2.3 U/l (p < 0.001). Total testosterone rose from 7.5 +/- 1.0 to 23.8 +/- 3.0 nmol/l (p < 0.001) without a concomitant change in sex hormone-binding globulin level. Those treated with Letrozole 17.5 mg per week had an excessive LH response. CONCLUSION: Short-term Letrozole treatment normalized serum testosterone levels in all obese men. The clinical significance of this intervention remains to be established in controlled, long-term studies.

Prevention of weight gain in type 2 diabetes requiring insulin treatment.

BACKGROUND: Patients with type 2 diabetes who are failing on oral agents will generally gain a large amount of body fat when switched to insulin treatment. This adverse effect may be related to chronic hyperinsulinism induced by long-acting insulin compounds. AIM: To test the concept that regain of glycaemic control can be achieved without causing weight gain, using a regimen free of long-acting insulin. METHODS: In a 3-month open-label pilot study including 25 patients with moderate overweight and secondary failure, we investigated whether nocturnal glycaemic control could be achieved with glimepiride administered at 20:00 hours. The starting dose was 1-2 mg, with subsequent titration up to a maximum of 6 mg. Rapid-acting insulin analogues were used three times daily to regain postprandial glucose control. RESULTS: Glycaemic control at 3 months was established with glimepiride in a dose of 4.4 +/- 0.3 mg/day (mean +/- standard error of the mean), and a total daily insulin dose of 24.1 +/- 2.6 IU. Fasting glucose levels decreased from 12.7 +/- 0.6 mmol/l to 8.1 +/- 0.3 mmol/l (p < 0.001), and target levels were reached in 14 of 25 patients (56%). Mean HbA1c decreased from 10.5 +/- 0.4 to 7.7 +/- 0.2% (p < 0.001). Symptomatic nocturnal hypoglycaemia was not reported. Body weight did not change (85.7 +/- 3.6 kg vs. 85.7 +/- 3.3 kg, p = 0.99). CONCLUSION: The data suggest that this new approach may be useful in about 50% of type 2 diabetes patients presenting with failure on maximal oral treatment.

Glomerular hyperfiltration in insulin-dependent diabetes mellitus is correlated with enhanced growth hormone secretion.

Enhanced GH secretion and hyperglycemia are suggested to play a role in the pathogenesis of glomerular hyperfiltration in insulin dependent diabetes mellitus. In this study we measured the GH response to GHRH (1 microgram/kg body weight), metabolic control, and renal function in 44 patients in order to explore a possible association between these parameters. Hyperfiltration [glomerular filtration rate (GFR) > 130 ml/min/1.73 m2] was present in 21 patients and normofiltration in 23. The duration of diabetes, plasma concentrations of renin, catecholamines, insulin-like growth factor-1 and blood glucose during renal function measurements were not different. GH response was significantly higher in patients with hyperfiltration. There was a positive relation between GH response and GFR (r = 0.51, P < 0.001) and effective renal plasma flow (r = 0.39, P < 0.01). GFR was correlated with insulin dose (r = 0.48, P < 0.001). There was no difference in glycosylated hemoglobin between the two groups. Patients with hyperfiltration used more insulin, had more frequent blood glucose values below the threshold level for activation of GH secretion, and had greater glycemic excursions than patients with normofiltration. The results suggest that GH hypersecretion and glomerular hyperfiltration are related and they support the possibility of a linkage between GH hypersecretion and glucose variability.

Different hepatobiliary effects of oral and transdermal estradiol in postmenopausal women.

Estrogen-replacement therapy is important for the prevention of postmenopausal osteoporosis. However, oral synthetic and conjugated estrogens increase biliary cholesterol saturation index and risk of gallstone disease. To examine whether transdermal estrogen administration could avoid these adverse effects, 17 postmenopausal women were treated with transdermal estradiol (Estraderm TTS; Ciba-Geigy, Arnhem, The Netherlands), 100 micrograms/day for 4 weeks, and after 1 month without therapy, with oral estradiol (Progynova; Schering, Weesp, The Netherlands), 2 mg/day for 4 weeks. The increase in the serum estradiol level was much higher during transdermal than oral estradiol administration. On the contrary, the increase in the serum estrone level was much more pronounced during oral treatment. Both modes of treatment led to a similar reduction of urinary calcium excretion. A highly significant decrease in serum phosphate levels was found during transdermal therapy. Biliary cholesterol saturation index did not change during transdermal therapy (mean +/- SEM, 1.25 +/- 0.06 before and 1.22 +/- 0.07 at the end of transdermal therapy; P = NS). A slight increase in cholesterol saturation index that did not reach statistical significance was found during oral therapy (1.28 +/- 0.09 before and 1.36 +/- 0.09 during oral treatment). However, the subgroup of women with strong increases in serum estrone levels during oral estradiol therapy (greater than 0.5 pmol/mL; n = 8) generally had increased biliary cholesterol saturation index, a decrease in relative percentage chenodeoxycholic acid in bile, and increased serum sex hormone-binding globulin levels during oral treatment. Cholesterol monohydrate crystals were never found in duodenal biles during either treatment. This study indicates that transdermal estradiol does not induce lithogenic bile. On the contrary, oral estradiol leads to lithogenic bile in a subgroup of women with strong increases in serum estrone levels during oral treatment.

Twice daily insulin therapy in patients with type 2 diabetes and secondary failure to sulphonylureas.

In 26 type 2 diabetic patients with failure to diet and sulphonylureas (fasting blood glucose levels greater than 8.0 mmol/l) the effects of insulin therapy on blood glucose control, islet B-cell function and plasma lipids were studied. Age was 58 +/- 11 (SD) yr, median duration of diabetes 6.5, range 1-24 yr, and body mass index 24.5, range 18.9-36.3 kg/m2. Six patients were obese. Therapy comprised twice daily injections of intermediate-acting insulin with additional fast-acting insulin when necessary. After six months, insulin dose was 39 +/- 10 U in the non-obese patients. Their fasting (14.0 +/- 2.7 mmol/l) and post-prandial blood glucose (17.9 +/- 4.5 mmol/l) and glycosylated haemoglobin (HbA1, 13.0 +/- 2.0%) declined to 7.7 +/- 1.6 mmol/l, 10.6 +/- 2.6 mmol/l and 9.5 +/- 1.0%, respectively (p less than 0.001). Median body weight increased by 3.7 kg (p less than 0.001). The changes in body weight correlated well with the changes in fasting blood glucose (r = -0.75, p less than 0.01) and HbA1 (r = -0.73, p less than 0.01). Fasting plasma insulin increased (p less than 0.01), whereas fasting plasma C-peptide and C-peptide release after glucagon did not change. Free fatty acids, LDL-cholesterol, total and VLDL-triglycerides showed a significant (p less than 0.05) decrease during insulin treatment. In the six obese patients insulin dose after six months was 44 +/- 18 U. Fasting blood glucose fell from 11.3 +/- 2.2 to 8.8 +/- 2.7 mmol/l (p less than 0.01), and HbA1 decreased from 10.7 +/- 1.1% to 9.8 +/- 1.3% (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized crossover study of sulphonylurea and insulin treatment in patients with type 2 diabetes poorly controlled on dietary therapy.

In 13 non-obese patients with Type 2 diabetes mellitus who failed to achieve adequate blood glucose control on dietary treatment (fasting blood glucose 13.4 +/- 2.7 (+/- SD) mmol l-1, glycosylated haemoglobin 13.0 +/- 1.7%), the effects of 6 months insulin or sulphonylurea therapy on blood glucose control and lipid metabolism were compared in a randomized crossover study. Three patients, who showed a clear improvement on insulin (median glycosylated haemoglobin fell from 14.7 to 8.6%), withdrew from the study prematurely because of subjective and objective signs of hyperglycaemia after crossover from insulin to sulphonylurea. Daily dose after 6 months was 2000 mg tolbutamide (n = 3), 18 +/- 1 mg glibenclamide (n = 7), or 34 +/- 3 U insulin. On insulin, fasting (8.0 +/- 1.9 mmol l-1) and postprandial blood glucose (10.4 +/- 2.7 mmol l-1), and glycosylated haemoglobin (9.5 +/- 1.1%) were lower than on sulphonylurea (11.0 +/- 3.4 mmol l-1, 14.4 +/- 4.8 mmol l-1 and 11.0 +/- 2.5%, respectively, p less than 0.05 in each case). Median increase in body weight was greater on insulin (4.2 vs 1.1 kg, p less than 0.05). Six patients experienced improved well-being on insulin compared with sulphonylurea. Median plasma non-esterified fatty acids decreased from 825 mumol l-1 to 476 mumol l-1 (sulphonylurea) and 642 mumol l-1 (insulin, both p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Factitious diabetes mellitus as part of Munchausen's syndrome.

The patient presented here was known to have been suffering from diabetes mellitus for 3 yr, when the suspicion arose that we were dealing with a factitious disease. The coincidence of several other factitious illnesses led us to the diagnosis of Munchausen's syndrome, self-inflicted diabetes mellitus being part of this syndrome.

Limitations of diet therapy in patients with non-insulin-dependent diabetes mellitus.

UNLABELLED: Sixty-one patients with non-insulin-dependent diabetes mellitus and fasting blood glucose of 12.0 +/- 0.6 mmol/l were studied before and after dietary treatment in an outpatient setting. At the start of the study 33 patients were obese (body mass index greater than 27.0 kg/m2). Twenty patients were newly diagnosed, median known duration of diabetes in the others was 5 years. Beta-cell function was measured by the release of C-peptide after i.v. injection of 1 mg glucagon (area under the curve of C-peptide = AUC-cp), as well as calculated according to the formulae of Matthews. Insulin action was estimated by measurement of fasting blood glucose, insulin and free fatty acids (FFA) concentrations. Non-obese patients showed more severe beta-cell deficiency than the obese ones (AUC-cp 2586 +/- 158 vs. 3294 +/- 277 pmol/l per 15 min), and did not improve in metabolic control during treatment. In the obese patients three response patterns to treatment were observed: weight loss and improvement in metabolic control accompanied primarily with increased beta-cell function or increased insulin action, or worsening of metabolic control. Those with less impaired beta-cell function and shorter known duration of diabetes showed the most favourable response. IN CONCLUSION: non-obese type 2 diabetes patients with fasting glucose levels above 10 mmol/l do not improve on dietary treatment alone; in obese type 2 diabetics weight reduction is essential and results in metabolic improvement, irrespective of the preceding fasting blood glucose concentrations. Improved beta-cell function as well as increased insulin action are responsible for this improvement.

Intestinal lymphangiectasia in systemic sclerosis.

Protein-losing gastroenteropathy is a well-recognized entity in systemic sclerosis, for which several mechanisms have been postulated. Acquired intestinal lymphangiectasia as a cause of increased intestinal protein loss has not previously been described in the literature. We report the first case of acquired intestinal lymphangiectasia in systemic sclerosis.

Studies on insulin secretion by monolayer cultures of normal and tumorous human pancreatic cells. Effects of glucose, somatostatin and SMS 201-995.

Recently, somatostatin analogs have been introduced which can be used clinically in the treatment of tumorous or functional hypoglycemia. In the present study we investigated in vitro the regulation, the degree of autonomy and the sensitivity to natural somatostatin and its analog SMS 201-995 of insulin secretion by monolayer cultures of human pancreatic cells obtained from patients with insulinomas and from a newborn with nesidioblastosis. All cultures released insulin upon the addition of dibutyryl-cAMP and calcium, demonstrating their intact viability. Insulin secretion from nontumorous pancreatic cells surrounding an insulinoma was dose-dependently stimulated by glucose. In contrast, insulin release by B cells from a patient with nesidioblastosis and from 2 insulinomas was not stimulated by the addition of glucose. Native somatostatin (SRIF) and the synthetic analog SMS 201-995 inhibited insulin secretion from all cultures. The inhibitory effects of SRIF and SMS in the culture from the nesidioblastosis tissue, could be reversed by the addition of 11.2 mmol glucose/l, but not in one of the insulinoma cultures. This demonstrates that some sensitivity to glucose is present in B cells from the nesidioblastosis tissue, despite the unresponsiveness to glucose alone. Insulin release by insulinoma cells was blocked by somatostatin, while it was inhibited to some extent only in the cultures of nontumor B cells and of cells from the nesidioblastosis tissue. In conclusion, it was shown that insulin release by the cultured B cells obtained from several pathological conditions differed with regard to the autonomy of hormone release (glucose sensitivity) and the sensitivity to somatostatin and its analog.

Disparate effects of ACTH (1-24) and corticosterone on lipoprotein lipase in rat adipose tissue.

The effects of corticosterone and ACTH(1-24) on lipoprotein lipase (LPL) activity of rat epididymal fat tissue were studied. Hypercorticism induced by s.c. administration of 10 mg corticosterone acetate for 3 days led to a decrease in LPL activity. This decrease could be prevented by treatment of the rats simultaneously with synthetic ACTH(1-24). Adrenalectomy also reduced LPL activity. Corticosterone and ACTH(1-24) treatment had a similar effect on LPL activity in adrenalectomized and intact rats. These results indicate that ACTH(1-24) may affect adipose tissue LPL in the rat by a mechanism in which corticosterone is not involved.

Effects of synacthen on lipid metabolism in the perfused epididymal fat pad of the rat.

Rats were treated with Synacthen, a synthetic corticotrophin analogue, to induce hypercorticism. The epididymal fat pad was selectively cannulated and perfused. In fasted rats acetone ether powder lipoprotein lipase (LPL) activity rose during treatment to levels found in fed controls. In fed animals no further rise in LPL activity was observed during Synacthen treatment. However, the heparin-elutable LPL activity did not change during this treatment in fasted nor fed animals. Pharmacologic levels of insulin in the perfusion medium caused an increase in heparin-releasable LPL activity as a percentage of total fat pad LPL activity (15% v 48%). Hydrolysis of chylomicrons was higher in fasted three days treated animals then in controls (10 +/- 4% v 2 +/- 2%). In this group a higher uptake of liberated free fatty acids was found (2.6 +/- 1.5% v 1.0 +/- 0.5% in controls). The increase in hydrolysis rate and uptake of fatty acids in the treated fasted animals could not be explained by an increase in releasable LPL activity. Fatty acid release from the fat pad was lower in treated animals than in controls (fasted and fed), basally as well as after adrenalin stimulation. The observation that the epididymal fat pad retains its weight during hypercorticism may therefore be ascribed to an increased influx of fatty acids from increased hydrolysis of TG-rich particles and to an inhibited efflux of fatty acids from the adipocyte. The discrepancy between the LPL activity extractable from an acetone ether powder and the heparin releasable LPL activity suggests impairment of the transport of LPL from the adipocyte to the heparin releasable pool at the endothelium.

On the use of a new somatostatin analogue in the treatment of hypoglycaemia in patients with insulinoma.

A novel potent analogue of somatostatin, the octapepide SMS 201-995 was tested as a therapeutic manoeuvre to prevent hypoglycaemia in patients with insulinoma. We investigated the acute effects of a single 50 micrograms dose of the analogue administered s.c. in three patients, comparing the results in two of them with those obtained after administration of saline (control) and native somatostatin. In addition two patients were treated for up to 5 d with two or three daily s.c. injections (daily dose of analogue ranging from 100 to 300 micrograms). In two of the three patients SMS 201-995 suppressed circulating insulin levels by more than 50% and increased plasma glucose to hyperglycaemic levels for 6-8 h after a single injection. No undesirable effects of the administration of the analogue were observed. As opposed to insulin suppression obtained with native somatostatin, no rebound increase in insulin levels was observed after administration of the analogue. We conclude that SMS 201-995 prevented hypoglycaemia in two out of three patients with insulinoma. The advantage of s.c. administration, the long duration of action and the absence of a rebound phenomenon give this analogue a place in the pre-operative management of patients with insulinoma.

Glucose tolerance during long term treatment with a somatostatin analogue.

Seven patients with active acromegaly were treated with SMS 201-995, an analogue of somatostatin, for one year, the maximum dose being 100 micrograms three times a day. Three patients had impaired glucose tolerance before treatment, due to insulin resistance in two and insulin deficiency in one. In all patients treatment with the analogue slightly increased postprandial glucose concentrations and suppressed insulin concentrations for two to two and a half hours after each injection; growth hormone concentrations decreased progressively with treatment. The patient with impaired glucose tolerance due to insulin deficiency developed diabetes mellitus after four months' treatment; concomitant treatment with glibenclamide resulted in a decreased glucose concentration and increased insulin concentration. This analogue of somatostatin had only minor side effects on glucose tolerance in patients with acromegaly and may be used in patients with impaired glucose tolerance provided that glucose concentrations are monitored closely.

A comparison among the growth hormone-lowering effects in acromegaly of the somatostatin analog SMS 201-995, bromocriptine, and the combination of both drugs.

The acute GH inhibitory effects of 50 micrograms SMS 201-995, a somatostatin analog, and 2.5 mg bromocriptine were compared in 17 acromegalic patients. SMS 201-995 suppressed plasma GH levels after 2-6 h to 5 micrograms/liter or less in 10 of these 17 patients, while bromocriptine did the same in only 5 of them. There was much variation in the responsiveness to both drugs in these patients, but the GH-lowering effect of 50 micrograms SMS 201-995 was significantly greater than that of 2.5 mg bromocriptine. SMS 201-995 and bromocriptine together significantly suppressed plasma GH levels in 2 of 3 acromegalic patients who were insensitive to both compounds when tested separately. We conclude that most acromegalic patients respond better to SMS 201-995, while a few patients are more sensitive to the GH-lowering effect of bromocriptine. In addition, the combination of SMS 201-995 and bromocriptine can be of value in a few acromegalic patients who do not respond to either drug alone.

Beta-blockade and carbohydrate metabolism: theoretical aspects and clinical implications.

The adrenergic control of carbohydrate metabolism is expressed at two levels: regulation of substrate flow, and interference with the secretion of hormones. Normally, this adrenergic regulatory system only plays a minor role. However, it is of great importance as an acute adaptation of the body to fight and flight. Under these circumstances, fuel fluxes increase almost instantaneously. Glycogenolysis and gluconeogenesis are responsible for increased hepatic glucose output. Increased fatty acid flux is brought about by stimulated adipose tissue lipolysis, which probably, as a secondary phenomenon, causes decreased peripheral glucose utilisation by the skeletal muscle mass. Cerebral glucose uptake accounts for half the body's basal glucose production. Since this glucose uptake is concentration-dependent only, hypoglycaemia rapidly leads to cerebral dysfunction. To guarantee cerebral glucose uptake, the body has a dual defense mechanism against hypoglycaemia: hormonal and metabolic counteraction. The first consists of the secretion of glucagon and (nor)epinephrine, the latter of hepatic autoregulation and alternative fuels for noncerebral tissues. In clinical practice, the inappropriate insulin-excess state forms the major cause of hypoglycaemia. There is, however, a second reason why patients with diabetes mellitus are at risk. Diabetes by itself leads to impaired glucagon secretion and, when autonomic neuropathy exists, to diminished (nor)epinephrine secretion. Thus, interference with the latter, such as administration of beta-blocking agents, further impairs hypoglycaemic counterregulation. In fact, numerous studies document delayed recovery from experimentally induced hypoglycaemia in diabetic patients receiving beta-blocking agents. However, using beta 1-selective blocking agents, mean recovery from hypoglycaemia in groups of diabetic patients demonstrates minor delay only.(ABSTRACT TRUNCATED AT 250 WORDS)