Showing papers by "K. G. M. M. Alberti published in 1992"

The short insulin tolerance test for determination of insulin sensitivity: a comparison with the euglycaemic clamp.

Abstract: The glucose clamp technique is currently regarded as the standard test for measuring insulin sensitivity against which other methods are compared but is unsuitable for routine screening of patients outside a hospital base There is thus a need for a simpler test to measure insulin sensitivity We have therefore compared the glucose disappearance rate KITT in the first 15 min of the insulin tolerance test (ITT) with the M and M/I values derived from the standard euglycaemic clamp in nine normal subjects and eight subjects with Type 2 (non-insulin dependent) diabetes mellitus and coexisting obesity All subjects underwent the ITT and euglycaemic clamp in random order Nine subjects later had a repeat ITT to determine the reproducibility of the test In the ITT, 01 U kg-1 body weight, human Actrapid insulin was given as an IV bolus and simultaneous arterialized and venous blood samples were obtained every minute for 15 min The first order rate constant for the disappearance of glucose KITT over the period 3-15 min was taken as a measure of insulin sensitivity The euglycaemic clamp was performed with an insulin infusion of 50 mU kg-1 h-1 for 120 min and a variable rate glucose infusion to maintain blood glucose concentration at 05 mmol l-1 below fasting level to minimize the effect of endogenous insulin secretion The ratio of the mean rate of glucose infused (M, mumol kg-1 min-1) to the plasma insulin over the last 30 min of the clamp was taken as a measure of tissue sensitivity to insulin (M/I) assuming endogenous glucose output was suppressed(ABSTRACT TRUNCATED AT 250 WORDS)

A survey of lower limb amputation in diabetic patients

Abstract: A retrospective survey of non-traumatic and non-neoplastic lower limb amputations in Newcastle upon Tyne during 1989-91 was performed. Hospital data were cross-checked with the local limb fitting centre to ensure 100% ascertainment. The diabetic patients were found to be 39% of amputees and 42% of operations (all levels). Incidence of diabetes amputation was 5.7 per 100,000 population per year. Fifteen percent of the diabetic patients had diabetes first diagnosed when they were admitted for amputation. For the known diabetes patients, 46% were under diabetes care by general practitioners only. Forty-seven percent of the patients who were under the care of a hospital service for diabetes had incomplete foot examination and assessment. Mortality rate within 30 days after diabetic amputation was 10% and median life expectancy following amputation was 22 months. It seems likely that assessment and management of the diabetic foot remains suboptimal in Newcastle, and that protocols and audit of care could lead to improvements without additional resources.

Metabolic Effects of Suppression of Nonesterified Fatty Acid Levels With Acipimox in Obese NIDDM Subjects

Abstract: NEFAs characteristically are elevated in obese NIDDM patients in both the basal state and after insulin. This elevation might aggravate glycemic control both by decreasing peripheral glucose disposal (glucose-fatty acid cycle), and by increasing HGO. Thus, lowering plasma NEFA levels might improve carbohydrate metabolism. We therefore measured HGO and fuel use (by indirect calorimetry) both in the basal state and during the last 30 min of a hyperinsulinemic clamp (0.025U · kg−1 · h−1) in 8 obese NIDDM patients (BMI 34.8 ±1.0 kg/m2) after complete overnight suppression of plasma NEFA levels with acipimox, a new nicotinic acid analogue. After acipimox, mean basal plasma NEFA and glycerol levels were lower than control values (0.11 ± 0.02 vs. 0.65 ±0.04 mM, P < 0.001; and 16 ± 3 vs. 68 ± 7 μM, P = 0.004, respectively) and were accompanied by a fall in lipid oxidation (acipimox vs. placebo: 16.1 ±1.2 vs. 38.8 ± 2.4 mg · m−2 · min−1; P < 0.001) and a rise in glucose oxidation (91.1 ± 6.2 vs. 54.1 ± 9.0 mg · m−2 · min−1; P = 0.002). Basal HGO and fasting plasma glucose levels were lower (94.1 ± 9.2 vs. 118.5 ± 9.5 mg · m−2 · min−1 P = 0.01; and 8.3 ± 1.2 vs. 9.8 ± 1.2 mM; P < 0.001), respectively. Serum insulin levels were similar during the clamps (44.2 ± 4.9 vs. 48.2 ± 5.7 μU/L; NS), but despite this, HGO was suppressed more after acipimox (18.2 ± 7.6 vs. 49.7 ± 12.9 mg · m−2 · min−1; P < 0.01), and the metabolic clearance rate for glucose was higher (101.98 ± 19.34 vs. 75.43 ± 9.94 ml · m−2 · min−1; P < 0.05). In conclusion, prolonged overnight suppression of lipolysis and lipid oxidation in obese NIDDM lowers fasting blood glucose and HGO and increases peripheral and hepatic sensitivity to insulin in obese NIDDM patients.

A double blind study of the effect of acipimox on serum lipids, blood glucose control and insulin action in non-obese patients with type 2 diabetes mellitus.

Abstract: Hyperlipidaemia, in particular raised concentrations of serum triglycerides, together with raised plasma non-esterified fatty acid concentrations, is common in patients with Type 2 (non-insulin-dependent) diabetes mellitus and may be associated with insulin insensitivity. Thirty non-obese Type 2 diabetic patients (15 controlled with diet alone and 15 with diet plus oral sulphonylurea therapy) were therefore recruited to take part in a double-blind, randomized, crossover comparison of acipimox (250 mg three times daily for 3 months) and placebo. Serum lipids, blood glucose control, insulin sensitivity, and glucose tolerance were measured before and after each treatment period. There was a significant decrease in serum triglycerides (2.05 +/- 1.08 vs 2.91 +/- 1.75: p < 0.005), cholesterol (5.66 +/- 1.02 vs 6.26 +/- 1.17: p = 0.0005), and apoprotein B (1.32 +/- 0.23 vs 1.44 +/- 0.25: p < 0.05) while HDL cholesterol and apoprotein A-1 concentrations were unchanged. There was no change in blood glucose control measured by fasting glucose, insulin, and HBA, concentrations, but there was a significant improvement in insulin action assessed by glucose-insulin infusion. Although plasma non-esterified fatty acid concentrations were lower during the oral glucose tolerance test after acipimox, there was no difference in either the peak or 2-h plasma glucose concentrations and the total area under the glucose curve did not change. Acipimox was well tolerated and no patients withdrew from the study for drug-related symptoms. Thus, acipimox effectively lowers serum cholesterol and triglycerides in patients with Type 2 diabetes without adversely altering blood glucose control, and appears to improve insulin sensitivity.

Relation between insulinemia, body mass index, and lipoprotein composition in healthy, nondiabetic men and women.

Abstract: Altered lipoprotein composition may be a better predictor of cardiovascular disease than modestly increased serum lipid concentrations, although possible interactions between lipoprotein composition, obesity, and insulinemia have not been fully elucidated. Therefore, we investigated the association between different measures of insulinemia and lipoproteins in 297 healthy Caucasian men (body mass index [BMI] less than 27 in 233, greater than 27 [obese] in 64) and 295 healthy Caucasian women (BMI less than 25 in 198, greater than 25 [obese] in 97). Associations observed in both obese and nonobese men and women were between increasing tertiles of most insulin measures and serum triglyceride concentrations (p = 0.079-0.004) and the ratio of low density lipoprotein to high density lipoprotein cholesterol (p = 0.094-0.008). Graded reductions in the high density lipoprotein cholesterol to apolipoprotein A-I ratio were also recorded in obese women, with increasing tertiles of fasting (p = 0.014-0.007) and postglucose load (p = 0.001) serum insulin levels, after correcting for BMI and triglyceride concentrations. Less marked graded increases in the triglyceride to apolipoprotein B ratios were recorded in obese women with increasing tertiles of fasting (p = 0.001-0.006) and postglucose challenge (p = 0.081) insulinemic measures. In men with normal or slightly elevated cholesterol levels (fasting serum cholesterol less than 6.5 mmol/l), hyperapobetalipoproteinemia was recorded with increasing tertiles of insulinemia (p = 0.006, correcting for BMI and triglyceride concentrations), as well as in subjects with hypertriglyceridemia (fasting serum triglycerides greater than 1.70 mmol/l) (p = 0.004, correcting for BMI and age). Hyperinsulinemia and insulin resistance are associated with altered lipoprotein composition in obese women, presumably reflecting a complex interplay between sex hormones, body mass, and insulin action. Insulin resistance appears to be more associated with apolipoprotein B concentrations in men. The hyperinsulinemic nondiabetic subject may be at increased risk of cardiovascular disease because of altered concentrations of apolipoprotein concentrations and lipoprotein composition.

Acute metabolic and hormonal responses to the inhibition of lipolysis in non-obese patients with non-insulin-dependent (type 2) diabetes mellitus: effects of acipimox.

Abstract: 1. Increased rates of fatty acid oxidation are frequently observed in patients with non-insulin-dependent diabetes mellitus and may contribute to hyperglycaemia by both decreasing peripheral glucose disposal and, more importantly, by increasing the rate of gluconeogenesis and therefore hepatic glucose output. Despite this relationship between lipid and carbohydrate metabolism, fasting glucose concentrations do not fall acutely in patients with non-insulin-dependent diabetes mellitus when plasma non-esterified fatty acid concentrations and lipid oxidation rates are decreased, questioning the importance of this interaction to glycaemic control. We have therefore measured the acute changes that occur 120–150 min after administration of 500 mg of the anti-lipolytic agent acipimox in eight non-obese male patients with non-insulin-dependent diabetes mellitus. 2. After administration of acipimox, lipolysis was inhibited as reflected by lower plasma non-esterified fatty acid (0.05 ± 0.02 versus 0.55 ± 0.05 mmol/1, P 3. We conclude that an acute decrease in fatty acid oxidation results in a switch to oxidation of glucose at the expense of glycogen stores, but apparently does not increase peripheral glucose uptake. Hepatic glucose output and fasting blood glucose concentration are maintained by an acute counter-regulatory response which presumably increases glycogen breakdown. Inhibitors of lipolysis and lipid oxidation are therefore more likely to lower fasting blood glucose concentration in the glycogen-depleted state.

Effect of acute inhibition of lipolysis on operation of the glucose-fatty acid cycle in hepatic cirrhosis

Abstract: Hepatic cirrhosis is frequently associated with glucose intolerance and insulin resistance, but the mechanisms underlying the insulin insensitivity are unknown. Plasma concentrations of nonesterified fatty acids (NEFA) are typically elevated in cirrhosis, and the glucose-fatty acid cycle provides a mechanism by which fatty acids may play a role in regulating glucose metabolism. We have therefore investigated the effect of acute inhibition of lipolysis, using the nicotinic acid analogue, acipimox, in 10 male patients with cirrhosis. All subjects were studied in the postabsorptive state after a 10- to 12-hour fast and were given either acipimox 250 mg or a placebo orally 2 hours before a 75-g oral glucose tolerance test (OGTT) and an infusion of insulin (50 mU/kg/h) and glucose (6 mg/kg/min) (insulin sensitivity tests [IST]). The drug was taken in a double-blind crossover design for each test. During the 2 hours following acipimox, there were rapid decreases in plasma NEFA, glycerol, and 3-hydroxybutyrate, confirming inhibition of lipolysis, while there were significant decreases in glucose, insulin, and C-peptide (P

Gliclazide: metabolic and vascular effects--a perspective.

Abstract: Gliclazide is a second-generation sulfonylurea that is widely used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM). It has been recommended for use on the basis of both its metabolic and nonmetabolic effects. It has a clear beneficial effect on metabolic control in NIDDM. Blood glucose and lipid levels are lowered. The glucose-lowering effects are secondary to both enhanced insulin secretion and a decrease in insulin resistance. The former is due to closure of a K+ adenosine triphosphate (ATP) channel in the beta cell. The mechanism whereby insulin action on the liver and muscle are potentiated remains unknown. It does not appear to involve the insulin receptor, and although glycogen synthase activation is enhanced, this is probably not specific. It has proven difficult to separate the metabolic effects of gliclazide from the effects of improved control. The metabolic actions are probably also shared with other sulfonylureas. Gliclazide also has beneficial effects on platelet behavior and function and on the endothelium, in addition to improving free radical status. These effects should be beneficial for the prevention of diabetic microangiopathy and macroangiopathy. Some evidence has appeared for the prevention of deterioration of diabetic retinopathy, but results are variable and more convincing studies are required. Many of the nonmetabolic effects of gliclazide appear to be unique to this agent. Gliclazide thus appears to be a reasonable choice in the treatment of NIDDM with diet failure, both from the metabolic and nonmetabolic standpoint.

Lipid and lipoprotein metabolism in familial combined hyperlipidaemia during treatment of sporadic phaeochromocytoma: a case study.

Abstract: Lipid metabolism was evaluated during management of phaeochromocytoma in a 41 year old non-obese post-menopausal women with familial combined hyperlipidaemia. The main effect of the excess catecholamine secretion on lipid metabolism was increased lipolytic activity, lower serum triglyceride and increased HDL cholesterol concentrations, compared with findings following removal of the tumour. Before removal of the tumour, the use of beta blockers alone led to marked deterioration of the hyperlipidaemic state, and combined alpha and beta blockade additionally led to a marked reduction in fat oxidation and lipoprotein lipase activity. Overactivity of the adrenergic system leads to changes in lipid metabolism in phaeochromocytoma. Treatment of the phaeochromocytoma may lead to worsening of hyperlipidaemia pre-existing in such individuals.

The effects of human proinsulin on glucose turnover and intermediary metabolism in insulin-dependent-diabetes mellitus.

Abstract: We have compared the action of human proinsulin and insulin on glucose turnover, intermediary carbohydrate, and lipid metabolism in insulin-dependent-diabetic (IDDM) subjects. Six, young, weight-matched (23 +/- 2 kg-2) IDDM subjects underwent separate hyperinsulinemic euglycemic clamps. Three, low dose, iv infusions of both insulin and proinsulin were used to construct dose response curves. The proinsulin infusions were chosen to give steady state levels approximately or equal to 20-fold higher on a molar basis than insulin, based on previous findings that proinsulin has only 5-10% the biological potency of insulin. Hepatic glucose production, measured using [6'6'2H2]glucose, was suppressed equally by proinsulin and insulin at the three dose levels; (I1) 2.8 +/- 0.7 (P1) 3.3 +/- 0.6, (I2) 2.3 +/- 0.9 (P2) 3.3 +/- 1.1, (I3) -2.0 +/- 1.7 (P3) -1.1 +/- 0.6 mumol/kg min-1. Percentage elevation of glucose disposal was significantly increased during the insulin infusions compared to proinsulin; (I1) 132 +/- 12 ...