Association between bone characteristics and cardiovascular risk factors among adults in selected urban areas in Selangor, Malaysia.

INTRODUCTION: Cardiovascular disease and osteoporosis (OP) have been shown to have similar risk factors but studies have demonstrated contradictory results with regards to their associations. This study evaluated relationships between bone characteristics and cardiovascular risk factors among adults in selected urban areas in Malaysia. MATERIALS AND METHODS: A cross-sectional study was performed involving 331 subjects between 45-90 years recruited at a health screening programme. Sociodemographic and clinical characteristics were recorded. Biochemical analyses on fasting blood samples and dual energy X-ray absorptiometry scan to determine bone mineral density (BMD) were performed. RESULTS: Increased waist circumference (WC) was protective for abnormal BMD status (osteopenia and OP). Males with increased high-density lipoprotein cholesterol (HDL) were more likely to be osteoporotic. WC, fasting blood glucose (FBG) and triglyceride (TG) were positively associated with BMD at all sites but was gender specific. In contrast, WC was negatively associated with trabecular bone score (TBS) for females but this association became attenuated when adjusted for fat percentage. HDL and MetS were negatively and positively associated with BMD, respectively in males. CONCLUSION: The cardiovascular risk factors of raised WC, FBG, TG and low HDL were significantly associated with increased BMD with skeletal site and gender specific differences after adjusting for confounders. However, a higher WC was associated with a weaker skeletal microstructure reflected by lower TBS in females driven by fat percentage. A higher BMD was demonstrated among MetS individuals. These findings suggest that adiposity may have a protective effect on BMD.

Development of the Asia Pacific Consortium on Osteoporosis (APCO) Framework: clinical standards of care for the screening, diagnosis, and management of osteoporosis in the Asia-Pacific region.

Guidelines for doctors managing osteoporosis in the Asia-Pacific region vary widely. We compared 18 guidelines for similarities and differences in five key areas. We then used a structured consensus process to develop clinical standards of care for the diagnosis and management of osteoporosis and for improving the quality of care. PURPOSE: Minimum clinical standards for assessment and management of osteoporosis are needed in the Asia-Pacific (AP) region to inform clinical practice guidelines (CPGs) and to improve osteoporosis care. We present the framework of these clinical standards and describe its development. METHODS: We conducted a structured comparative analysis of existing CPGs in the AP region using a "5IQ" model (identification, investigation, information, intervention, integration, and quality). One-hundred data elements were extracted from each guideline. We then employed a four-round Delphi consensus process to structure the framework, identify key components of guidance, and develop clinical care standards. RESULTS: Eighteen guidelines were included. The 5IQ analysis demonstrated marked heterogeneity, notably in guidance on risk factors, the use of biochemical markers, self-care information for patients, indications for osteoporosis treatment, use of fracture risk assessment tools, and protocols for monitoring treatment. There was minimal guidance on long-term management plans or on strategies and systems for clinical quality improvement. Twenty-nine APCO members participated in the Delphi process, resulting in consensus on 16 clinical standards, with levels of attainment defined for those on identification and investigation of fragility fractures, vertebral fracture assessment, and inclusion of quality metrics in guidelines. CONCLUSION: The 5IQ analysis confirmed previous anecdotal observations of marked heterogeneity of osteoporosis clinical guidelines in the AP region. The Framework provides practical, clear, and feasible recommendations for osteoporosis care and can be adapted for use in other such vastly diverse regions. Implementation of the standards is expected to significantly lessen the global burden of osteoporosis.

Secondary prevention of fragility fractures in Asia Pacific: an educational initiative.

The Asia -Pacific Bone Academy (APBA) Fracture Liaison Service (FLS) Focus Group educational initiative has stimulated activity across the Asia -Pacific region with the intention of supporting widespread implementation of new FLS. In 2017, the APBA FLS Focus Group developed a suite of tools to support implementation of FLS across the Asia-Pacific region as a component of a multi-faceted educational initiative. This article puts this initiative into context with a narrative review describing the burden of fragility fractures in the region, the current secondary fracture prevention care gap and a summary of emerging best practice. The results of a survey to evaluate the impact of the APBA educational initiative is presented, in addition to commentary on recent activities intended to improve the care of individuals who sustain fragility fractures across the Asia -Pacific. A FLS Toolbox for Asia-Pacific was developed which included the following sections:1. The burden of fragility fractures in the Asia-Pacific region.2. A summary of evidence for FLS in the Asia-Pacific.3. A generic, fully referenced FLS business plan template.4. Potential cost savings accrued by each country, based on a country-specific FLS Benefits Calculator.5. How to start and expand FLS programmes in the Asia-Pacific context.6. A step-by-step guide to setting up FLS in countries in the Asia-Pacific region.7. Other practical tools to support FLS establishment.8. FLS online resources and publications.The FLS Toolbox was provided as a resource to support FLS workshops immediately following the 5th Scientific Meeting of the Asian Federation of Osteoporosis Societies (AFOS) held in Kuala Lumpur in October 2017. The FLS workshops addressed three key themes:• The FLS business case.• Planning the FLS patient pathway.• The role of the FLS coordinator in fragility fracture care management.A follow-up survey of 142 FLS workshop participants was conducted in August-September 2018. The survey included questions regarding how FLS were developed, funded, the scope of service provision and the support provided by the educational initiative. Almost one-third (30.3%) of FLS workshop participants completed the survey. Survey responses were reported for those who had established a FLS at the time the survey was conducted and, separately, for those who had not established a FLS. Findings for those who had established a FLS included:• 78.3% of respondents established a multidisciplinary team to develop the business case for their FLS.• 87.0% of respondents stated that a multidisciplinary team was established to design the patient pathway for their FLS.• 26.1% of respondents stated that their FLS has sustainable funding.• The primary source of funding for FLS was from public hospitals (83.3%) as compared with private hospitals (16.7%).Most hospitals that had not established a FLS at the time the survey was conducted were either in the process of setting-up a FLS (47%) or had plans in place to establish a FLS for which approval is being sought (29%). The primary barrier to establishing a new FLS was lack of sustainable funding. The APBA FLS Focus Group educational initiative has stimulated activity across the Asia-Pacific region with the intention of supporting widespread implementation of new FLS. A second edition of the FLS Toolbox is in development which is intended to complement ongoing efforts throughout the region to expedite widespread implementation of FLS.

Evaluating compliance with the care standard of proactively assessing bone health in patients with diabetes: a pilot audit of practice across Asia by the Asia Pacific Consortium on Osteoporosis (APCO).

This pilot audit explored how bone health is assessed patients with diabetes in diverse centres across Asia. Only 343 of 1092 (31%) audited patients had a bone health assessment, 27% of whom were diagnosed with osteoporosis. Quality improvement strategies are needed to address gaps in patient care in this area. PURPOSE: The Asia Pacific Consortium on Osteoporosis (APCO) Framework outlines clinical standards for assessing and managing osteoporosis. A pilot audit evaluated adherence to clinical standard 4, which states that bone health should be assessed in patients with conditions associated with bone loss and/or increased fracture risk; this report summarises the audit findings in patients with diabetes. A secondary aim was to assess the practicality and real-world use of the APCO bone health audit tool kit. METHODS: Eight centres across Asia participated in the pilot audit, selecting diabetes as the target group. Participants reviewed their practice records for at least 20 consecutively treated patients with the target condition. Questions covered routine investigations, bone health assessment, osteoporosis diagnosis, and patient referral pathways. Data were summarised descriptively. RESULTS: The participants represented public hospitals, university medical centres, and private clinics from India, Malaysia, Pakistan, Singapore, Taiwan, and Vietnam that see an estimated total of 95,000 patients with diabetes per year. Overall, only 343 of 1092 audited patients (31%) had a bone health assessment. Osteoporosis was subsequently diagnosed in 92 of 343 (27%) patients. CONCLUSION: Bone health was not assessed in most patients with diabetes. The results provide insight into current practices across diverse Asian centres and demonstrate the practical value of the audit tool kit. Participant feedback has been used to improve the tool kit. Results of this pilot audit are being used in the respective centres to inform quality improvement projects needed to overcome the gap in patient care.

Defects of insulin action and skeletal muscle glucose metabolism in growth hormone-deficient adults persist after 24 months of recombinant human growth hormone therapy.

We have previously reported that GH-deficient (GHD) adults are severely insulin resistant. In the present study, we determined the effects of 6 months (n = 7) and 24 months (long-term; n = 11) of recombinant human GH (rhGH) therapy (approximately 0.22 IU/kg.week) on body composition and fasting biochemical (including lipid) parameters, and baseline and insulin-stimulated: 1) rates of hepatic glucose production, total glucose disposal (Rd), total glycolysis (GF) and glucose storage (GS); and 2) skeletal muscle glucose processing [using the euglycemic-hyperinsulinemic (approximately 60 mU/L) clamp technique with tritiated glucose infusion coupled with skeletal muscle biopsies]. To allow baseline comparison, these measurements were also obtained from 10 control subjects matched to the pretreated GHD adults for age, sex, and body mass index. Long-term rhGH therapy in GHD adults induced significant improvements in fat mass, abdominal fat mass and fat free mass, and reductions in fasting cholesterol and low-density lipoprotein-cholesterol levels (P < 0.05-0.01 vs. pretreatment values). However, there was a significant increase in fasting insulin (13.1 +/- 0.9 vs. 8.6 +/- 1.1 mU/L; P < 0.01) and connecting peptide (0.56 +/- 0.05 vs. 0.41 +/- 0.06 nmol/L; P < 0.05). Although rates of baseline hepatic glucose production, GF, and GS were unchanged, the insulin-stimulated increment (delta) in Rd, GF, and GS remained markedly attenuated in the long-term rhGH-treated GHD adults [pretreatment: delta Rd 16.6 +/- 3.4, delta GF 3.0 +/- 1.2, delta GS 13.6 +/- 3.0 vs. 24 months of rhGH: delta Rd 17.2 +/- 3.3, delta GF 3.1 +/- 0.9, delta GS 14.1 +/- 2.5 vs. controls: delta Rd 42.6 +/- 4.3, delta GF 9.2 +/- 1.9, delta GS 35.9 +/- 4.5 mumol/kg fat free mass.min; P < 0.05-0.01 vs. controls]. Additionally, there was a sustained reduction in the insulin-stimulated skeletal muscle glycogen synthase fractional velocity (pretreatment: 0.29 +/- 0.03 vs. 24 months of rhGH: 0.24 +/- 0.03 vs. controls: 0.48 +/- 0.04; both P < 0.05 vs. controls), which was accompanied by a sustained 44% decrease in baseline glycogen content and a 70% increase in baseline im glucose concentrations in the presence of low-to-normal glucose 6-phosphate levels and persisting euglycemia. Stepwise regression analysis revealed that body weight and fasting free fatty acid and high-density lipoprotein (HDL)-cholesterol accounted for 82% of the variance in the insulin sensitivity index in long-term rhGH-treated adults, and that the 24-month fasting insulin-like growth factor 1 was a negative predictor of the change in insulin sensitivity (r = -0.82; P < 0.01). In conclusion, despite improvements in body composition and lipid profiles, the severe defects of in vivo insulin sensitivity and skeletal muscle intracellular glucose phosphorylation and glycogen synthase activity, which are associated with modestly elevated insulin-like growth factor 1 levels, normal free fatty acid levels, and the development of hyperinsulinemia, persist with long-term rhGH therapy.

Low density lipoprotein particle size in hypopituitary adults receiving conventional hormone replacement therapy.

Adults receiving conventional replacement therapy for hypopituitarism are known to have increased cardiovascular mortality. The aim of this study was to assess the lipid profiles of 30 hypopituitary adults compared with 2 case control groups, 1 matched for age, sex, and body mass index (BMI) and the second matched for age and sex only with a BMI representative of the general population. Fasting lipids, lipoproteins, and apoproteins (Apo) were determined by routine methods. Low density lipoprotein (LDL) particle size was determined by nondenaturing gradient gel electrophoresis. LDL size was significantly smaller in the hypopituitary group (25.9 +/- 0.1 nm) than in the BMI-matched (26.2 +/- 0.1 nm; P < 0.05) and standard control (26.3 +/- 0.1 nm; P < 0.01) groups. High density lipoprotein cholesterol levels in the hypopituitary group were significantly lower than those in the BMI-matched control group (1.13 +/- 0.06 vs. 1.34 +/- 0.06 mmol/L; P < 0.05) and the standard control group (1.38 +/- 0.06 mmol/L; P < 0.005). Apo A1 levels were also lower compared with those in the BMI-matched (122 +/- 6 vs. 137 +/- 4 mg/dL; P < 0.05) and the standard (143 +/- 4 mg/dL; P < 0.005) control groups. There was a trend toward higher triglyceride levels when the hypopituitary subjects were compared with the standard control group [1.4 (95% CI, 1.3-2.2) vs. 1.0 (95% CI, 0.9-1.4) mmol/L; P = 0.06]. These differences were more marked in the female subjects studied. No significant differences were noted in total cholesterol, LDL cholesterol, or Apo B levels. We conclude that hypopituitary patients receiving conventional replacement therapy have an atherogenic lipid profile characterized by small dense LDL, decreased high density lipoprotein cholesterol, and increased triglyceride levels, which may contribute to the excess cardiovascular mortality in this group.

Insulin resistance in growth hormone-deficient adults: defects in glucose utilization and glycogen synthase activity.

Fourteen GH-deficient (GHD) adults were compared with 12 age-, sex-, and body mass index-matched control subjects using a baseline tritiated glucose equilibration period and euglycemic-hyperinsulinemic (approximately 55 mU/L) clamp in conjunction with paired muscle biopsies for measurement of glycogen synthase fractional velocity (FV0.1). Despite similar basal rates of total glucose disposal (Rd), there was a 64% reduction in the insulin-stimulated rise (delta) in Rd in the GHD adults compared to that in controls [16.6 +/- 2.8 vs. 44.7 +/- 6.0 mumol/kg fat free mass (FFM)/min; P < 0.001], which was mainly due to a decreased glucose storage (GS) rate (delta GS, 12.6 +/- 2.9 vs. 39.5 +/- 7.5 mumol/kg FFM/min; P < 0.01). Furthermore, the insulin sensitivity indexes of Rd (0.39 +/- 0.07 vs. 0.85 +/- 0.11; P < 0.05) and GS (0.25 +/- 0.07 vs. 0.72 +/- 0.13 mumol/kg FFM/min per mU/L; P < 0.02) were reduced in GHD adults compared to the control values. The insulin sensitivity of the glycolytic pathway was also reduced by approximately 50% in GHD adults (P = 0.07 vs. controls). Insulin-stimulated FV0.1 was decreased in GHD adults (0.31 +/- 0.02 vs. 0.47 +/- 0.03; P < 0.005) despite similar basal FV0.1. Using multiple and stepwise regression analysis, duration of GH deficiency, fasting triglycerides and fasting insulin accounted for 67% of the variance in the insulin sensitivity index of Rd. In conclusion, the severe insulin resistance in GHD adults is mainly due to the inhibition of the GS pathway and glycogen synthase activity in peripheral tissues, which is related to the duration of GH deficiency, fasting triglycerides, and fasting insulin.

Insulin secretion in growth hormone-deficient adults: effects of 24 months' therapy and five days' acute withdrawal of recombinant human growth hormone.

Beta-cell function in growth hormone (GH)-deficient (GHD) adults is poorly documented. Beta-cell function was therefore studied in 10 GHD adults (age, 40+/-3 years; weight, 79.3+/-4.8 kg; body mass index [BMI], 27.5+/-1.3 kg x m(-2)) before and after 6- and 24-month recombinant human GH (rhGH) therapy (0.24 IU x kg(-1) x wk(-1)) compared with 10 age-, sex-, weight-, and BMI-matched control subjects. With rhGH therapy, fat-free mass (FFM) increased (48.2+/-4.9, 52.5+/-4.8, and 59+/-6.8 kg, respectively) and fat mass (FM) decreased (33.8%+/-2.8%, 28.0%+/-3.0%, and 29.4%+/-2.5%, respectively), as did serum cholesterol. Oral glucose tolerance initially deteriorated at 6 months, but improved toward the control value by 24 months. Fasting insulin (FI) increased significantly, as did the acute insulin response to oral glucose (deltaAIR(OGTT)/deltaG) at 30 minutes (FI: pretreatment 9.8+/-0.8, 6 months, 14.0+/-1.8, 24 months 12.5+/-1.6 v control 11.4+/-1.9 mU x L(-1); deltaAIR(OGTT)/deltaG: pretreatment 201+/-24, 6 months 356+/-41, 24 months 382+/-86 v control 280+/-47 mU x mmol(-1)). However, the acute insulin response to intravenous (IV) glucose (AIR(G)) and IV glucagon at euglycemia and hyperglycemia did not change with rhGH therapy and were similar to the control group values. Importantly, the expected reciprocal relationships (as observed for the control group) between the various insulin secretory parameters and insulin sensitivity (SI) either were not present or were statistically weak in GHD subjects, despite the 35% decrease in SI by 24 months of rhGH therapy. In particular, over time, there was an attenuation of insulin secretion with respect to the ongoing insulin resistance with rhGH therapy, particularly for AIR(G) at 24 months. After 5 days of rhGH withdrawal, insulin secretion decreased and SI improved in GHD subjects. It is concluded that the current long-term rhGH treatment regimens appear to impact on insulin secretion such that the normal relationships between insulin secretion and SI are altered despite the favorable impact on body composition and serum lipid profiles.

The effect of 24 months recombinant human growth hormone (rh-GH) on LDL cholesterol, triglyceride-rich lipoproteins and apo [a] in hypopituitary adults previously treated with conventional replacement therapy.

Hypopituitary adults receiving conventional hormone replacement therapy are reported to have increased cardiovascular mortality. Previous studies indicate that these patients have several abnormalities in lipoprotein metabolism, including reduced low density lipoprotein (LDL) uptake and impaired metabolism of triglyceride-rich lipoproteins. The effects of 24 months of 0.21 IU/kg per week recombinant growth hormone (rh-GH) on the lipoprotein profiles of 22 GH-deficient adults were studied. Samples were collected after a 12-h fast at baseline and 24 months. Total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, LDL cholesterol, apolipoprotein (apo) A, apo B and apo [a] were determined by routine laboratory methods. LDL particle size was determined by non-denaturing gradient gel electrophoresis. Visceral adiposity was determined by dual energy X-ray absorptiometry (DEXA). Insulin sensitivity was measured in a subset of 17 subjects using a two-stage hyperinsulinaemic-euglycaemic clamp. Significant reductions were observed in total cholesterol (5.3 +/- 0. 17 vs 4.9 +/- 0.23 mmol/l;P<0.05) and LDL cholesterol (3.4 +/- 0.17 vs 2.9 +/- 0.17 mmol/l; P<0.001) at 24 months when compared to baseline. No significant changes were observed in triglyceride level, HDL cholesterol level, apo B, apo A and LDL size. A significant increase in apo [a] [160 (96-416) vs 204 (127-534) U/l;P<0.05] was observed which appeared to be dose-dependent. Visceral adiposity was reduced significantly. Insulin sensitivity did not alter significantly. Replacement for 24 months with rh-GH has a differential effect on the lipid profile with a decrease in LDL, but little effect upon the metabolism of triglyceride-rich lipoproteins, manifested by unchanged triglyceride, HDL cholesterol levels and LDL size, despite the reduction in visceral adiposity. Conversely, apo [a], an independent risk factor for cardiovascular disease was increased. The ultimate effect of GH therapy upon cardiovascular mortality remains to be determined and may be dose-related.

Prevalence of glutamic acid decarboxylase antibodies amongst young Malaysian diabetics.

This study determined the prevalence of glutamic acid decarboxylase antibodies (GAD Ab) in a group of 926 young Malaysian diabetics of three ethnic groups, Malay, Chinese, and Indian. Patients were clinically diagnosed to be Type 1 or Type 2 before the age of 40 years. The overall GAD Ab positivity was 17.4% (161/926), significantly higher in the Type 1 than the Type 2 diabetics (35.5%, 116/329 vs. 7.5%, 45/597, P=0.0001). Compared to GAD Ab negative patients, seropositive diabetics were diagnosed at younger age (21.2+/-0.9 vs. 27.4+/-0.3 y, P=0.0001), had lower fasting (289+/-27.4 vs. 640+/-17.6 pmol/l, P=0.0001) and post-glucagon C-peptide levels (527+/-51.8 vs. 1030+/-28.9 pmol/l, P=0.0001). There were no racial differences in the prevalence of GAD Ab; of the total Type 1, 30.8, 36.4, and 39.4% were Malay, Chinese, and Indian diabetics, respectively and of the total Type 2, 8.8, 8.2, and 4.4% were Malay, Chinese, and Indian diabetics respectively. There was a curvilinear relationship between GAD Ab and the post-glucagon C-peptide levels, suggesting that GAD Ab do play a role in the beta-cells destruction and could be an important immune marker for the LADA group. This study reconfirmed previous reports that the autoimmune mechanisms in the Type 1 Asian diabetics are indeed different from the Caucasians, and further investigations should be carried out to explain the differences.

Treatment of chronic urticaria with thyroxine in an euthyroid patient with thyroglobulin and microsomal antibodies.

INTRODUCTION: The association of chronic urticaria and thyroid autoimmunity is not well recognised and the potential use of thyroxine in the treatment of chronic urticaria in patients with thyroid autoimmunity is even less well known. CLINICAL PICTURE: We report a case of chronic urticaria in an euthyroid patient with evidence of significantly elevated levels of thyroglobulin and microsomal antibodies. TREATMENT AND OUTCOME: Treatment with thyroxine has brought about clinical remission of the chronic urticaria but no change in the thyroid antibody levels could be demonstrated. CONCLUSION: Patients with chronic urticaria should be screened for evidence of thyroid autoimmunity. A closely monitored trial of thyroxine therapy for those who have thyroid autoimmunity can be rewarding.

A case report of primary hyperparathyroidism with severe bony involvement and nephrolithiasis.

INTRODUCTION: Although the majority of patients with primary hyperparathyroidism have a relatively asymptomatic benign disorder, there are patients who have a more aggressive disorder. CLINICAL PICTURE: We report a case of primary hyperparathyroidism presenting during pregnancy complicated by antepartum haemorrhage and severe prematurity. The diagnosis was made postpartum, when her problems rapidly progressed to result in severe neuromuscular weakness, bilateral pathological hip fractures as well as nephrolithiasis. TREATMENT: Surgical parathyroidectomy was performed. The underlying lesion was a large solitary parathyroid adenoma with cystic elements. CONCLUSION: Primary hyperparathyroidism is not an innocuous disease and can result in severe morbidity if left untreated.

The anaesthetic foot. A case of severe diabetic peripheral neuropathy.

Diabetic foot care is an important aspect of management. Self-care by the patient is of paramount importance. The case history described in this article highlights the absence of pain associated with peripheral neuropathy and the consequences of inadequate foot care by the patient.

Petrosal sinus sampling in the diagnosis of Cushing's syndrome: preliminary experience in University of Malaya Medical Centre.

Differentiating between Cushing's disease of pituitary origin and ectopic ACTH syndrome of extra-pituitary origin remains a major challenge to the clinician because of limitations in the diagnostic accuracy of the high-dose dexamethasone suppression test. Routine use of inferior petrosal sinus sampling (IPSS) is therefore advocated by some authors for these patients. We present our preliminary experience of IPSS in 7 consecutive patients with Cushing's disease and discuss how the results impacted on the patients' management.

Diabetes Mellitus in a Malaysian Teaching Hospital: Prevalence of Diabetes Mellitus and Frequency of Testing for Hypercholesterolaemia, Proteinuria and HbAlc.

We examined the prevalence of diabetes among inpatients in our hospital, the relationship of the diagnoses on admission to diabetes, and the frequency of testing for HbA1c as a marker of long-term glycaemic control, proteinuria, and hypercholesterolaemia. In addition, patients with raised laboratory plasma glucose without a know history of diabetes mellitus, were studied to see if these had been further evaluation. The overall prevalence of diabetes in our hospital was 25.% with the highest prevalence found (37.8%) on medical wards. 10.5% of admissions were due directly to diabetes and a further 58.9% of patients were admitted with illness which were significant related to diabetes. Overall testing rates for HbA31c, proteinuria, and hypercholesterolaemia were less than ideal (51.6, 73.4 and 45.% respectively). Less than 50% of patients without previously diagnosed diabetes but with high plasma glucose values had further evaluation for diabetes. In conclusion, this study has detected a high overall prevalence of diabetes among inpatients in an urban Malaysian hospital. Rates of testing for HbA51c, proteinuria, and hypercholesterolaemia, are disappointingly low, as is further evaluation of patients without known diabetes, but with elevated glucose values. More effective measures to improve the delivery of inpatient diabetes care are needed.

Growth hormone deficiency and cardiovascular risk.

It is now recognized that growth hormone (GH) deficiency in adults represents a distinct clinical syndrome that encompasses reduced psychological well-being as well as specific metabolic abnormalities. The latter features, which include hypertension, central obesity, insulin resistance, dyslipidaemia and coagulopathy, closely resemble those of metabolic insulin resistance syndrome. The increased cardiovascular morbidity and mortality demonstrated in these GH-deficient (GHD) adults reinforce the close association between the two syndromes. Replacement of GH in GHD adults has resulted in a marked reduction of central obesity and significant reduction in total cholesterol but little change in other risk factors, in particular insulin resistance and dyslipidaemia. The persistent insulin resistance and dyslipidaemia, together with the elevation of plasma insulin levels and lipoprotein (a) with GH replacement in these subjects are of concern. Long-term follow-up data are required to assess the impact of GH replacement on the cardiovascular morbidity and mortality of GHD adults. Further exploration of the appropriateness of the GH dosage regimens currently being employed is also indicated.

Insulin sensitivity in growth hormone (GH)-deficient adults and effect of GH replacement therapy.

Growth hormone (GH) deficiency in adults is characterized by central obesity, dyslipidemia, coagulopathy and glucose intolerance, all features of the "metabolic syndrome", explaining the increased cardiovascular morbidity and mortality associated with GH deficiency in adults. Employing the 2-step euglycemic-hyperinsulinemic clamp, we have demonstrated severe insulin resistance in GH-deficient adults, with a reduction in insulin-mediated glucose utilization of -50%. Basal glucose turnover and partitioning of whole body glucose utilization into glycolytic flux (GF) and glycogen synthesis/glucose storage (GS) pathways are normal, but insulin activation of these 2 pathways is reduced, predominantly in the GS pathway. Activation of muscle glycogen synthase by insulin is markedly decreased, as is glycogen content of muscle. Insulin-induced muscle hexokinase activity appears also to be attenuated in GH-deficient adults with raised intramuscular cellular glucose and normal-reduced concentrations of glucose-6-phosphate. Beta-cell function is not excessive in GH-deficient adults and is inappropriately low for the insulin resistance. Following treatment of GH-deficient adults with recombinant GH (rhGH), the insulin resistance is either unchanged or more pronounced by 3, 6 or 24 months of treatment, despite the significant reduction in general and central obesity. The GF and GS pathways and muscle glycogen synthase and hexokinase activities remain severely impaired. Abnormalities in free fatty acid (FFA) metabolism are present in rhGH-treated GH-deficient adults and correlate significantly with the degree of insulin resistance as do the concentrations of rhGH-induced insulin-like growth factor (IGF)-I, the post-basal insulinemia and the duration of the GHD, but is independent of obesity. In conclusion, long-term rhGH treatment in GH-deficient adults results in persistent insulin resistance and abnormalities in the GF and GS pathways due to reduced glycogen synthase and hexokinase activities, in the presence of an ongoing reduction of central obesity. We postulate that the insulin resistance is due to chronic rhGH-induced alterations in FFA metabolism, non-physiological levels of IGF-I and chronic basal hyperinsulinemia.

Ethnicity and glycaemic control are major determinants of diabetic dyslipidaemia in Malaysia.

AIMS: To define the prevalence of dyslipidaemia in young diabetic patients in Peninsular Malaysia and the contributory factors of dyslipidaemia in these subjects. METHODS: This is a cross-sectional study involving 848 young diabetic patients from seven different centres, with representation from the three main ethnic groups. Clinical history and physical examination was done and blood taken for HbA1c, fasting glucose, total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol and triglycerides. RESULTS: The overall lipids were suboptimal, worse in Type 2 diabetes mellitus (DM) patients compared with Type 1 DM patients. Of the Type 2 patients, 73.2% had total cholesterol > 5.20 mmol/l, 90.9% had LDL-cholesterol > 2.60 mmol/l, 52.6% had HDL-cholesterol < 1.15 mmol/l and 27.3% had serum triglycerides > 2.30 mmol/l. There were ethnic differences in the lipid levels with the Malays having the highest total cholesterol (mean 6.19 mmol/l), and the highest LDL-cholesterol (mean 4.16 mmol/l), while the Chinese had the highest HDL-cholesterol (geometric mean 1.24 mmol/l). Ethnicity was an important determinant of total, LDL- and HDL-cholesterol in Type 2 DM, and LDL- and HDL-cholesterol and triglycerides in Type 1 DM. Glycaemic control was an important determinant of total, LDL-cholesterol and triglycerides in both Type 1 and Type 2 DM. Waist-hip ratio (WHR) was an important determinant of HDL-cholesterol and triglycerides in both types of DM. Gender was an important determinant of HDL-cholesterol in Type 2 DM, but not in Type 1 DM. Socioeconomic factors and diabetes care facilities did not have any effect on the dyslipidaemia. CONCLUSIONS: The prevalence of dyslipidaemia was high especially in Type 2 DM patients. Ethnicity, glycaemic control, WHR, and gender were important determinants of dyslipidaemia in young diabetic patients. Diabet. Med. 18, 501-508 (2001)