Effects of growth hormone on insulin resistance and atherosclerotic risk factors in obese type 2 diabetic patients with poor glycaemic control

OBJECTIVE: We aimed to evaluate the combined effects of GH treatment and diet restriction on lipolysis and anabolism, insulin resistance and atherosclerotic risk factors in obese patients with type 2 diabetes mellitus (T2DM). SUBJECTS: This randomized, double-blind, placebo-controlled study included 24 obese T2DM patients (male : female = 12 : 12, mean age 53.7 +/- 7.2 years) with poor glycaemic control (fasting plasma glucose 10.673 +/- 1.121 mmol/l, HbA(1C) 9.9 +/- 2.3%). Sixteen of these patients were treated with recombinant human GH (1-1.5 units/day, 5 days/week) while undergoing diet restriction and exercise for 12 weeks. METHODS: Anthropometric and bioelectrical impedance measurements were undertaken to determine the lean body mass and total body fat. Computed tomography (CT) was performed to estimate visceral and subcutaneous fat distribution at the umbilicus level and the muscle area of the midthigh. Insulin resistance was measured by the insulin tolerance test (ITT) and by the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: The ratios VSR (visceral fat area/subcutaneous fat area) and VMR (visceral fat area/thigh muscle area) were significantly decreased in the GH-treated group compared to the control group. An increase in lean body mass was observed in the GH-treated group. Levels of total cholesterol, triglyceride, free fatty acid (FFA), fibrinogen, and plasminogen activator inhibitor-1 (PAI-1) were significantly decreased after GH treatment. Fasting glucose levels decreased similarly (P < 0.05 anova) in both groups during the treatment period. Fasting C-peptide levels significantly increased, whereas insulin levels significantly decreased, in the GH-treated group, but no changes were observed in the control group. The insulin sensitivity index (ISI) was significantly increased in the GH-treated group (1.3 +/- 1.4 vs. 1.9 +/- 1.0%/min, P < 0.05). CONCLUSIONS: GH treatment in obese T2DM patients with poor glycaemic control is beneficial in decreasing the amount of visceral fats, and may therefore result in improvements in insulin resistance, atherosclerotic risk factors and dyslipidaemia.     

Impaired vascular function during short-term poor glycaemic control in Type 1 diabetic patients.

AIM: To study the effects of short-term poor glycaemic control on vascular function in Type 1 diabetic patients. METHODS: Ten Type 1 diabetic patients, with diabetes duration of less than 10 years and normal urinary albumin excretion and ophthalmoscopy, were studied. All patients were examined after 48 h of good vs. poor glycaemic control within a 3-week period. Blood glucose was measured seven times daily for 2 days before each examination. External ultrasound was used to measure the dilatory response of the brachial artery to post-ischaemic increased blood flow (endothelium-dependent dilation) and to nitroglycerin (endothelium-independent dilation). Plasma concentration of von Willebrand factor antigen, adhesion molecules, vascular endothelial growth factor, homocystein and cholesterol were also measured. RESULTS: The median blood glucose levels in the 48 h before the examinations were [median (range), good vs. poor control]: 6.3 (5.0-7.6) vs. 15.9 (11.3-17.8) (mmol/l). The flow-associated vasodilation (% of baseline) was reduced during poor control: 102.7 (94.7-110.8) vs. 104.0 (99.6-118.5) (P < 0.05) as were the nitroglycerin-induced dilation (% of baseline): 114.5 (103.3-127.9) vs. 120.2 (106.8-148.0) (P < 0.05). P-von Willebrand factor antigen was high during poor control (kIU/l): 1.14 (0.73-1.84) vs. 0.86 (0.72-1.39) (P < 0.05) and so was P-vascular endothelial growth factor (ng/l): 288 (133-773) vs. 254 (90-383) (P < 0.05). CONCLUSIONS: Short-term (48 h) hyperglycaemia in Type 1 diabetic patients may disturb vascular function, possibly mediated through smooth muscle cell dysfunction as well as endothelial dysfunction. We suggest that prolonged and repeated episodes of hyperglycaemia could possibly lead to permanent vascular dysfunction and thereby development and progression of vascular complications in diabetes.     

Adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia: an unusual cause of Cushing's syndrome

Inappropriate ACTH secretion with bilateral diffuse or macronodular adrenal hyperplasia is the most common cause of Cushing's syndrome. This report describes a patient with Cushing's syndrome and feminization due to ACTH-independent bilateral macronodular adrenal hyperplasia. A 47-yr-old black man presented with Cushingoid features, diabetes mellitus, hypertension, impotence, and gynecomastia. Urinary cortisol and 17-hydroxycorticosteroid excretion were 94 nmol/mmol creatinine (normal, less than 32) and 5.8 mumol/mmol creatinine (normal, 0.6-3.6), respectively. Both decreased by less than 30% after administration of dexamethasone (8 and 16 mg/day), and urinary 17-hydroxycorticosteroid excretion did not increase after metyrapone (750 mg, orally, every 4 h for six doses). Plasma ACTH was undetectable (less than 1 pmol/L) and was not stimulated by administration of metyrapone or ovine CRH. Serum testosterone was 5.2 nmol/L (normal, 7-30), FSH was 5 U/L (normal, 3-18), LH was 2.8 U/L (normal, 1.5-9.2), and estrone was 767 pmol/L (normal, 55-240). Both adrenal glands were enlarged, with a total weight of 86 g (normal, 8-10), and contained multiple nodules (diameter, greater than 0.5 cm) composed of two active cell types, one of which was also observed between the nodules. Cushing's syndrome with feminization due to ACTH-independent bilateral macronodular adrenal hyperplasia is an unusual process of unknown etiology that should be included with the other known causes of Cushing's syndrome.     

Smoking cessation and glycaemic control in type 2 diabetic patients

Aim:  To elucidate the relationship between glycaemic control, blood pressure and body-weight change after smoking cessation in type 2 diabetic patients.
Methods:  We examined HbA_1c, blood pressure and body weight in 15 type 2 diabetic patients before, 6 and 12 months after quitting smoking. Sixteen type 2 diabetic patients who did not quit smoking served as control.
Results:  Body weight slightly increased after quitting smoking. Although HbA_1c levels showed no change in the control group, those in patients who quit smoking significantly increased (6.8 ± 0.3% before quitting smoking; 7.4 ± 0.3% 6 months after quitting smoking, p < 0.05; 7.8 ± 0.4% 12 months after quitting smoking, p < 0.001). Fasting blood glucose also increased in patients who quit smoking. The increase in body weight after quitting smoking did not correlate with the deterioration of glycaemic control. Diastolic blood pressure showed no change in control, whereas that in patients who quit smoking increased at month 12 (69 ± 3 vs. 76 ± 3 mmHg, p < 0.01). The increase in HbA_1c at month 12 after quitting smoking correlated with body mass index before quitting smoking ( r  = 0.72, p < 0.005) and serum triglyceride before quitting smoking ( r  = 0.68, p < 0.01).
Conclusions:  Glycaemic control and diastolic blood pressure deteriorated in type 2 diabetic patients after quitting smoking. Type 2 diabetic patients who want to stop smoking need a caution to prevent deterioration of glycaemic control and blood pressure after quitting smoking.     

Predictors of glycaemic control in indigent patients presenting with diabetic ketoacidosis

AIM: To derive predictors of good glycaemic control in patients presenting with diabetic ketoacidosis (DKA) followed prospectively in a specialized clinic. METHODS: One hundred and sixty-one adult patients were admitted during a 31-month period and followed for at least 12 months. After 1 year, the patients were classified into three groups: good control (GC) (HbA1c < or = 7%), intermediate control (IC) (HbA1c 7-9%) and poor control (PC) (HbA1c > 9%). Characteristics of patients in the three groups were compared both at baseline and during follow-up. RESULTS: At 12 months, 36% of the patients were classified as GC, 27% as IC and 37% as PC. GC patients had higher fasting serum C-peptide levels 0.7 +/- 0.54 compared to 0.38 +/- 0.29 and 0.16 +/- 0.21 nmol/l, respectively, for the IC and PC patients (p < 0.0001). A higher proportion GC patient had a C-peptide level greater than 0.33 nmol/l than that for IC and PC patients (86, 61 and 19%, respectively; p < 0.0001). Exogenous insulin was safely discontinued in 50, 30 and 3% of patients, respectively, in the GC, IC and PC groups (p < 0.0001). Compliance with life-style interventions was higher in the GC than that in IC and PC patients (87, 41 and 5%, respectively; p < 0.0001). In the logistic regression analysis, predictors of good glycaemic control were having baseline fasting serum C-peptide value > or =0.33 mmol/l, OR: 3.01 (95% CI 1.07-8.55, p = 0.03) and compliance with life-style interventions OR 12.66 (95% CI 3.73-51.57, p = 0.0001). CONCLUSION: Among adult patients with DKA, significant predictors of good glycaemic control are preserved beta-cell function and compliance with life-style modifications.     

Sociodemographic determinants of glycaemic control in young diabetic patients in peninsular Malaysia

Recent studies have shown that good glycaemic control can prevent the development of diabetic complications in type 1 and type 2 diabetes. We wished to observe the glycaemic control in patients from different centres in Peninsular Malaysia and the factors that determine it. We recruited 926 patients with diabetes diagnosed before age 40 years from seven different centres, with proportionate representation from the three main ethnic groups. Clinical history and physical examination were done and blood taken for HbA1c and fasting glucose. The overall glycaemic control was poor with geometric mean HbA1c of 8.6% whilst 61.1% of the patients had HbA1c greater than 8%. Glycaemic control in patients with type 2 diabetes varied between various centres and ethnic groups, with the best control obtained in Chinese patients. Significant predictors of HbA1c in both type 1 and type 2 diabetes include access to nurse educators, ethnic background and WHR. In type 2 diabetes, use of insulin was a significant predictor, while in type 1 diabetes, household income was a significant predictor. Socioeconomic status did not have a significant effect in type 2 diabetes. There were no significant differences in the glycaemic control in patients with different educational status. In conclusion, glycaemic control in big hospitals in Malaysia was poor, and was closely related to the availability of diabetes care facilities and ethnic group, rather than socioeconomic status.     

Medication non-adherence and poor glycaemic control in patients with type 2 diabetes mellitus

AimsHyperglycemia causes generation of free radicals which leads to oxidative stress and apoptosis in various cells. The present study was undertaken to investigate the correlation between oxidative stress and apoptotic markers in lymphocytes of diabetic patients with chronic non healing wounds.MethodsThirty healthy, thirty uncontrolled type 2 diabetes mellitus (T2DM) and thirty uncontrolled T2DM with chronic, non healing, neuropathic diabetic foot patients were included in this study. Indices of oxidative stress inside the lymphocyte lysate were estimated by measuring content of superoxide dismutase (SOD), Catalase, Glutathione and malonaldialdehyde (MDA). Protein expression studies of pro and anti apoptotic markers were carried out to elucidate their possible involvement in diabetic context.ResultsSOD and MDA activity was significantly higher in the lymphocytes of diabetic patients having chronic, non healing diabetic wound as compared with healthy (p < 0.001); whereas catalase and GSH activity was significantly reduced (p < 0.001) in the same group. Expressions of pro apoptotic markers (Caspase-3, Fas and Bax) were significantly higher whereas reduced expression of anti-apoptotic marker (Bcl-2) were obtained in lymphocytes of diabetic and non diabetic individuals.ConclusionsHyperglycemia confers pro apoptotic manifestations which are mostly through altered indices of oxidative stress within lymphocytic milieu.     

Improved glycaemic control in obese diabetic ob/ob mice using N-terminally modified gastric inhibitory polypeptide

Gastric inhibitory polypeptide (GIP) is an important insulin-releasing hormone of the enteroinsular axis which is rapidly inactivated by the exopeptidase dipeptidyl peptidase (DPP) IV. The present study has examined the ability of Tyr(1)-glucitol GIP to be protected from plasma degradation and to enhance insulin-releasing and antihyperglycaemic activity in 20- to 25-week-old obese diabetic ob/ob mice. Degradation of GIP by incubation at 37 degrees C with obese mouse plasma was clearly evident after 3 h (35% degraded). After 6 h, more than 61% of GIP was converted to GIP(3-42) whereas N-terminally modified Tyr(1)-glucitol GIP was resistant to degradation in plasma (>99% intact after 6 h). The formation of GIP(3-42) was almost completely abolished by inhibition of plasma DPP IV with diprotin A. Effects of GIP and Tyr(1)-glucitol GIP were examined in overnight-fasted obese mice following i.p. injection of either peptide (20 nmol/kg) together with glucose (18 mmol/kg) or in association with feeding. Most prominent effects were observed in the former group where plasma glucose values at 60 min together with the area under the curve (AUC) for glucose were significantly lower following GIP (AUC, 874+/-72 mmol/l.min; P<0.01) or Tyr(1)-glucitol GIP (770+/-134 mmol/l.min; P<0.001) as compared with administration of glucose alone (1344+/-136 mmol/l.min). This was associated with a significantly greater and more protracted insulin response following Tyr(1)-glucitol GIP than GIP (AUC, 491+/-118 vs 180+/-33 ng/ml.min; P<0.05). Administration of Tyr(1)-glucitol GIP also enhanced the glucose-lowering ability of 50 units/kg insulin (218.4+/-30.2 vs insulin alone 133.9+/-16.2 mmol/l.min; P<0.05). These data demonstrate that Tyr(1)-glucitol GIP displays resistance to plasma DPP IV degradation in a commonly used animal model of type 2 diabetes, resulting in enhanced antihyperglycaemic activity and insulin-releasing action in vivo.     

Improvement in glycaemic control with rosiglitazone/metformin fixed-dose combination therapy in patients with type 2 diabetes with very poor glycaemic control

OBJECTIVE: Traditional first-line intervention in patients with type 2 diabetes and very poor glycaemic control is insulin therapy or high doses of sulfonylureas if there is no evidence of volume depletion. This study explored the safety and efficacy of open-label treatment with rosiglitazone and metformin (RSG/MET) fixed-dose combination therapy (AVANDAMET) in patients with type 2 diabetes with very poor glycaemic control, to better characterize the magnitude of glycated haemoglobin (A1c) reduction after 24 weeks of therapy. METHODS: In this multicentre, open-label trial, 190 patients with an A1c greater than 11% or fasting plasma glucose (FPG) greater than 15 mmol/l were included after failing to meet glycaemic entry criteria for a primary double-blind, controlled, randomized study. Unless tolerability issues arose, eligible patients initiated RSG/MET 4 mg/1000 mg fixed-dose combination therapy and were up-titrated in increments of 2 mg/500 mg at 4-week intervals to a daily dose of 8 mg/2000 mg or the maximum tolerated dose. Patients were assessed for efficacy and safety at five visits over a 24-week period. The primary efficacy end point was change from baseline in A1c at week 24. Secondary efficacy end points included the proportion of patients achieving defined A1c targets, change from baseline to week 24 in FPG and insulin sensitivity. RESULTS: The majority of patients (78%) completed 24 weeks of open-label treatment. At week 24, clinically significant mean reduction in A1c from 11.8 to 7.8% (mean reduction, 4.0 +/- 2.2%; p < 0.0001) and mean FPG reduction from 16.9 to 9.2 mmol/l (mean reduction, 7.7 +/- 4.4 mmol/l; p < 0.0001) were observed. A clinically significant reduction in FPG (5.2 mmol/l) was observed after 4 weeks of treatment with RSG/MET fixed-dose combination therapy. Despite a high mean baseline A1c of 11.8%, 33% of patients achieved treatment goal of A1c less than or equal to 6.5% at week 24, and 44% achieved an A1c less than 7% at week 24. RSG/MET fixed-dose combination was well tolerated, with a low incidence of hypoglycaemia (2%) and mean increase in weight from baseline of 2.6 +/- 5.2 kg, and few patients withdrew (2.6%) because of an adverse event. CONCLUSIONS: RSG/MET fixed-dose combination therapy was effective as initial therapy in patients with type 2 diabetes and very high levels of A1c and/or FPG, as demonstrated by robust and relatively rapid improvements in glycaemic control. RSG/MET fixed-dose combination was well tolerated as first-line therapy with no new tolerability issues identified.     

Cushing's syndrome in pregnancy: an overview

Cushing's syndrome (CS) during pregnancy is a rare condition with fewer than 150 cases reported in the literature. Adrenal adenomas were found to be the commonest cause, followed by Cushing's disease. The gestation dramatically affects the maternal hypothalamic-pituitary-adrenal axis, resulting in increased hepatic production of corticosteroid-binding globulin (CBG), increased levels of serum, salivary and urinary free cortisol, lack of suppression of cortisol levels after dexamethasone administration and placental production of CRH and ACTH. Moreover, a blunted response of ACTH and cortisol to exogenous CRH may also occur. Therefore, the diagnosis of CS during pregnancy is much more difficult. Misdiagnosis of CS is also common, as the syndrome may be easily confused with preeclampsia or gestational diabetes. Because CS during pregnancy is usually associated with severe maternal and fetal complications, its early diagnosis and treatment are critical. Surgery is the treatment of choice for CS in pregnancy, except perhaps in the late third trimester, with medical therapy being a second choice. There does not seem to be a rationale for supportive treatment alone.     

Cyclic Cushing's syndrome: an overview

Cyclic Cushing's syndrome (CS) is a disorder in which glucocorticoid levels are alternately normal and high, the latter occurring in episodes that can last from a few days to several months. It is more common in children than in adults. Cyclic CS may be either of the two different forms of CS (ACTH-dependent or -independent CS). Clinically, it may present with one or many symptoms, depending on the duration of disease activity and the timing of the fluctuations. A serotoninergic influence, cyclic changes in central dopaminergic tone, spontaneous episodic hemorrhage in the tumor, and the action of inflammatory cytokines with antitumor properties are some of the mechanisms suggested to explain the physiopathology of this phenomenon but the exact mechanism remains to be clarified. The cyclic pattern of hypercortisolism can delay the final diagnosis of CS and make it difficult to interpret the results of dynamic tests. Patients may have paradoxical responses to dexamethasone that can reflect increasing or decreasing levels of endogenous activity. Hormone assessments have to be repeated periodically when a diagnosis of CS is suspected. The cyclic pattern can also interfere with medical treatment because patients may show unexpected clinical and biochemical signs of hypocortisolism when cortisol secretion cyclically returns to normal, so an accurate follow-up is mandatory in these patients.     

Neointimal proliferation within carotid stents is more pronounced in diabetic patients with initial poor glycaemic state

Aims/hypothesis We studied the influence of initial hyperglycaemia on neointimal proliferation within carotid Wallstents.Methods A total of 112 patients were followed by duplex sonography after carotid stenting for 24 months. Patients were assigned to three groups: non-diabetic subjects (group A) and diabetic patients, who were assigned according to their baseline HbA₁c values, to group B1(HbA₁c6.5%) or group B2 (HbA₁c>6.5%).Results At baseline the groups did not differ with respect to other vascular risk factors and residual stenosis on angiograms. The maximal thickness of the layer between the stent and the perfused lumen was measured at the duplex follow-ups. At 3 months the typical ultrasonic structure of the neointima was clearly discernible. From this point on, group B2 differed significantly (p<0.001) compared with B1 and A with respect to the maximal thickness of neointima and the time course of its ingrowth: group A vs B1 vs B2 was 0.51±0.39 vs 0.52±0.33 vs 0.56±0.35 at 3 months, 0.91±0.27 vs 0.90±0.38 vs 1.14±0.48 at 6 months, 1.02±0.24 vs 0.97±0.34 vs 1.21±0.44 at 12 months and 1.09±0.23 vs 1.10±0.31 vs 1.23±0.37 at 24 months.Conclusion/interpretation Initial hyperglycaemia seems to be a predictor of more pronounced neointimal proliferation after carotid stenting independent of diabetes. As intimal hyperplasia is known to be responsible for stent restenosis, strict optimisation of the hyperglycaemic state should be aimed at before elective carotid artery stenting.Abbreviations CCDS Colour coded duplex sonography - CHD coronary heart disease - PAOD peripheral arterial occlusive disease - CCA common carotid artery - ICA internal carotid artery - IMT intima-media thickness - UKPDS United Kingdom Prospective Diabetes Study Group     

Adrenocorticotrophin-independent unilateral macronodular adrenal hyperplasia occurring with myelolipoma: an unusual cause of Cushing's syndrome

We report a case of Cushing's syndrome due to ACTH-independent unilateral macronodular adrenal hyperplasia that occurred with a myelolipoma and propose that these two entitles may be linked to the production of an adrenal growth factor.     

Hyperventilation syndrome: a frequent cause of chest pain.

Chest pain is frequently a prominent symptom of the hyperventilation syndrome (HVS) and must be distinguished from angina pectoris due to coronary atherosclerotic heart disease (CAHD). The association between hyperventilation and chest pain may be apparent if psychoneurotic traits or anxiety are present. Many patients with HVS are not overtly anxious or neurotic, but in the great majority, a careful history and physical examination will indicate whether chest pain is due to HVS or CAHD. The failure to make this clinical differential diagnosis, which often leads to unnecessary coronary angiography, should not be as frequent as generally experienced. Fifteen of 95 consecutive patients had chest pain and additional typical HVS symptoms. Reassurance and detailed explanation about the cause of the chest pain gave significant relief, so that all patients were less symptomatic 24 to 44 months later, and none had developed new signs or symptoms to suggest that symptomatic CAHD had been overlooked. The risk and expense of coronary angiography was avoided.