Showing papers by "K. G. M. M. Alberti published in 1996"

Mechanism of anti-lipolytic action of acipimox in isolated rat adipocytes.

Abstract: Acipimox is commonly used to treat hyper-triglyceridaemia in non-insulin-dependent diabetic patients, but its precise mechanism of action has yet to be elucidated. We examined the in vitro effects of acipimox on the lipolytic regulatory cascade in epididymal adipocytes isolated from Wistar rats. Acipimox inhibited the lipolytic rate stimulated by adenosine deaminase (1 U/ml) in a concentration-dependent manner, reaching a near-basal value at 10 Μmol/l acipimox. Lipolysis activated by sub-maximal levels of isoproterenol in combination with adenosine deaminase (20 mU/ml) was significantly (p 0.05) inhibition. These findings suggested that the anti-lipolytic mechanism regulated by adenosine may also be regulated by acipimox. Acipimox diminished the intracellular cyclic AMP level produced by 25 nmol/l isoproterenol in the presence of adenosine deaminase (20 mU/ml) in a concentration-dependent manner. At the same level of stimulation, acipimox inhibited the cyclic AMP-dependent protein kinase activity ratio and lipolytic rate over the same concentration range, with significant (p<0.05) reductions occurring at and above, 0.5 Μmol/l and 10 Μmol/l acipimox, respectively. Western blotting showed that upon lipolytic stimulation (1 U/ml adenosine deaminase; 100 nmol/l isoproterenol) a threefold increase in the lipolytic rate was accompanied by a significant (p<0.05) rise in hormone-sensitive lipase associated with the lipid fraction. Acipimox (1 mmol/l) and insulin (1 nmol/l) re-distributed hormone-sensitive lipase back to the cytosol, with a corresponding significant (p<0.05) loss from the fat cake fraction of adipocyte homogenates. In conclusion, the anti-lipolytic action of acipimox is mediated through suppression of intracellular cyclic AMP levels, with the subsequent decrease in cyclic AMP-dependent protein kinase activity, leading to the reduced association of hormone-sensitive lipase with triacylglycerol substrate in the lipid droplet of adipocytes.

Human insulin receptor substrate-1: variant sequences in familial non-insulin-dependent diabetes mellitus.

Abstract: The aetiology of NIDDM is uncertain, although family and twin studies indicate an important role for genetic factors in disease onset. The function and position of IRS-1 within the insulin signalling pathway make it a prime candidate gene for the development of insulin resistance and NIDDM. Insulin resistant families were identified by studying unaffected first degree relatives from families with 2 or more living NIDDM subjects. Insulin sensitivity was determined in the relatives using the insulin tolerance test, and 15 families were identified as insulin resistant. One NIDDM subject from the 10 most resistant families was selected and the entire coding region of IRS-1 analysed by SSCP analysis. Four normoglycaemic subjects with no family history of diabetes served as controls. Five variant sequences of IRS-1 were identified with the NIDDM subjects; 2 silent polymorphisms at codons 235 (GGG to GGA) and 893 (CCG to CCC): 2 non-conservative mutations (Ala513Pro; Gly972Arg) and a codon deletion (Ser681-7 to Ser681-6). The influence of the non-conservative mutations alone, and in combination with other abnormalities of the insulin signalling pathway on peripheral insulin action, remains to be determined.

Diabetes mellitus as a cause of death in sub-Saharan Africa : Results of a community-based study in Tanzania

Abstract: The aim of this study was to determine the contribution of diabetes mellitus to all-cause mortality and diabetes mortality rates in adults 15 years and above living in one urban and two rural areas of Tanzania (Dar es Salaam, Hai and Morogoro Rural Districts). The three surveillance populations comprised 307,912 persons. Prospective monitoring of all deaths between 1 June 1992 and 31 May 1995 was carried out. Cause of death was determined by verbal 'autopsy' conducted with relatives of the deceased. In total, 4299 deaths were recorded in children (aged < 15 years) and 8054 in adults. In children there were no reported deaths associated with diabetes (due to or in children with diabetes). The adult male mortality rates associated with diabetes were 34, 30, and 15 per 100,000 per year in Dar es Salaam, Hai and Morogoro Rural Districts respectively. The figures in women were 21, 18, and 4 per 100,000 per year, respectively. The percentages of all adult male deaths associated with diabetes were 2.6%, 2.1% and 0.7% respectively. In women the percentages were 1.7%, 1.8%, and 0.2% respectively. Acute metabolic complications, infection, and stroke each accounted for approximately 30% of all diabetic deaths. Thus diabetes mortality rates varied between the three surveillance areas, being lowest in the poorest rural area. Rates were higher in men in all areas. While care is required in the comparison of mortality rates between countries, it was noteworthy that Tanzania, a country with a low diabetes prevalence, had diabetes mortality rates which were higher than or comparable to rates in Mauritius and the United States. Most patients died from preventable causes, indicating a need for improved case-management of diabetic emergencies as well as better detection and treatment of hypertension.

Variant sequences of the Hexokinase II gene in familial NIDDM

Abstract: Hexokinase II (HKII) plays a central role in the intracellular metabolism of glucose in skeletal muscle, catalysing the phosphorylation of glucose to glucose 6-phosphate. It is therefore considered to be a potentially important candidate gene in the development of insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM). The aim of this study was to screen the HKII gene for mutations in NIDDM subjects from insulin-resistant families. Insulin sensitivity was assessed in unaffected first degree relatives from families with two or more living NIDDM subjects, and 15 families were identified as being insulin resistant. In 15 NIDDM subjects (one from each family) and 4 normoglycaemic control subjects, all 18 exons of the HKII gene were amplified by the polymerase chain reaction, and the products screened for mutations using a combination of single-stranded conformational polymorphism analysis and direct sequencing. Six sequence variations were detected in the NIDDM subjects; four silent polymorphisms [GAT vs GAC at codon 251 in exon 7, AAT vs AAC at codon 692 in exon 15, CCG vs CCC at codon 736 in exon 15, and CTG vs CTA at codon 766 in exon 16]; a single base change [T→C], 22 base pairs distal to the exon-intron junction of exon 17 in the 5′-splice donor; and a single amino acid substitution [Gln142→His] in exon 4, which was identified in 6 of the 15 NIDDM subjects. The frequency of the mutated codon 142 allele however, was comparable between NIDDM subjects with familial NIDDM (n=56) and normoglycaemic control subjects (n=48) (18.8% and 14.6% for NIDDM subjects and control subjects respectively; χ2=0.6, p>0.25). In addition, measures of insulin sensitivity were comparable in normal glucose tolerant subjects with (n=20) and without (n=40) the codon 142 polymorphism. In conclusion: (1) mutations in the coding regions of the HKII gene are unlikely to be major determinants in the development of insulin resistance and familial NIDDM; although (2) the influence of the codon 142 mutation in combination with other abnormalities of the insulin-signalling pathway on insulin action remain to be addressed.

Are body mass or insulin resistance independently associated with cardiovascular risk factors in non-diabetic elderly Nigerians?

Abstract: The aim was to establish whether risk factors for cardiovascular disease (CVD) are positively and independently associated with fasting insulin and/or body mass and waist-hip ratio in healthy elderly Nigerian subjects. Fasting plasma glucose, insulin, total cholesterol, triglycerides, blood pressure, and basal insulin resistance (HOMA method) were measured in 500 healthy elderly (> or = 55 years) Nigerian volunteers (295 men, 205 women). Associations between blood pressure, triglycerides or cholesterol and fasting insulin, HOMA, body mass index (BMI) or waist-hip ratio were examined using linear regression. Age was controlled for in all analyses. In men, diastolic and systolic blood pressure were strongly associated with BMI, while there was no evidence of an independent relationship with fasting insulin or HOMA. Triglycerides were strongly associated with waist-hip ratio, with a weaker independent association with HOMA but not fasting insulin; fasting insulin and HOMA showed strong independent associations with total cholesterol. In women diastolic and systolic blood pressure were also strongly associated with BMI, but there was an independent relationship with fasting insulin for diastolic blood pressure and a less significant (p = 0.057) one for systolic blood pressure. Triglycerides were significantly associated with BMI but none of the other variables; there were no significant associations with cholesterol. There was no evidence of interaction between fasting insulin or HOMA and BMI or waist-hip ratio. The results suggest the hypotheses that in this population BMI or waist-hip ratio are stronger determinants of blood pressure and triglyceride levels than fasting insulin or HOMA, and that where insulin does play a role its effects are separate and additive.