Changes in insulin and lipid metabolism in males with asymptomatic hyperuricaemia

Abstract. Objectives. To define the effect of asymptomatic hyperuricaemia on various facets of glucose, insulin, and lipoprotein metabolism. Design. Case control study in health volunteers. Setting. The volunteers for this study were selected on the basis of their laboratory results from a larger population participating in a general survey in one large factory. Subjects. The study population consisted of 40 healthy males: 20 with asymptomatic hyperuricaemia (serum uric acid concentration equal to or greater than 420 mmol l^?1) and 20 with normal serum uric acid concentrations (180–320 mmol l^?1). The two groups were similar in terms of age, general obesity (estimated by body mass index), smoking and alcohol intake, and estimate of work and leisure time activity. Interventions. All subjects received a 75 g oral glucose challenge, with blood taken before and at frequent intervals thereafter. Main outcome measures. Fasting plasma glucose, insulin, and lipid concentrations and plasma glucose and insulin responses to the oral glucose challenge. Results. By selection, mean (± sem ) serum uric acid concentration was higher in the hyperuricaemic individuals (454 ± 7 vs. 274 ± 12 mmol l^?1). In addition, the plasma insulin response to oral glucose was increased in individuals with asymptomatic hyperuricaemia (P < 0.005) as were both systolic (136 ± 3 vs. 126 ± 3 mmHg, P < 0.05) and diastolic (91 ± 1 vs. 82 ± 1, P < 0.01) blood pressure. Furthermore, subjects with asymptomatic hyperuricaemia were dyslipidaemic (higher plasma TG and cholesterol and lower HDL-cholesterol concentrations) as compared to the normouricaemic control group (P < 0.07–0.005). Conclusions. These results provide a possible explanation for the well-known association of hyperuricaemia with coronary heart disease, as well as suggesting that hyperuricaemia be added to the cluster of metabolic and haemodynamic abnormalities associated with insulin resistance and/or hyperinsulinaemia and designated as Syndrome X.     

The set point for maternal glucose homeostasis is lowered during late pregnancy in the rat: the role of the islet beta-cell and liver

Summary The aim of this study was to determine the effects of late pregnancy on the ability of insulin to suppress maternal hepatic glucose production in the rat. Unlike in most previous studies, suppression of hepatic glucose production was measured at levels of glycaemia above the relatively hypoglycaemic basal pregnant level. Glucose kinetics were measured using steady-state tracer methodology in chronically catheterised, conscious virgin control and pregnant rats, firstly, during basal and low-dose hyperinsulinaemic euglycaemic clamp conditions and secondly, during a three-step glucose infusion protocol (glucose infusion rates of 0, 60 and 150 μmol · kg⁻¹· min⁻¹). During the clamps, plasma glucose levels were not different (6.1 ± 0.4 vs 6.5 ± 0.3 mmol/l, pregnant vs virgin; N. S.), but plasma insulin levels were higher in the pregnant rats (242 ± 30 vs 154 ± 18 pmol/l, pregnant vs virgin; p < 0.05) most probably due to stimulated endogenous insulin release in this group. Hepatic glucose production was suppressed from basal levels by 41 % in virgin and 90 % in pregnant rats. During the glucose infusion studies, at matched insulin levels (147 ± 10 vs 152 ± 14 pmol/l), but at plasma glucose levels which were much lower in the pregnant rats (5.5 ± 0.2 vs 8.4 ± 0.6 mmol/l, pregnant vs virgin; p < 0.0001), hepatic glucose production was shown to be suppressed by a similar degree in both groups (41 ± 5 vs 51 ± 5 % from basal, pregnant vs virgin; N. S.). Both the plasma insulin and percentage suppression of hepatic glucose production dose responses to plasma glucose were markedly shifted to the left indicating that the plasma glucose set point is lowered in pregnancy. In conclusion, suppression of hepatic glucose production by insulin is not impaired and the set point for plasma glucose homeostasis is lowered during late pregnancy in the rat. [Diabetologia (1996) 39: 785–792] Received: 2 October 1995 and in final revised form: 1 February 1996     

Forearm Substrate Exchange during Hyperinsulinaemic Hypoglycaemia in Normal Man

To assess muscle substrate exchange during hypoglycaemia, 8 healthy young male subjects were studied twice during 2 h of hyperinsulinaemic euglycaemia followed by 4 h of (1) hypoglycaemia (plasma glucose < 2.8 mmol l^?1), and (2) euglycaemia. Insulin was infused at a rate of 1.5 mU kg^?1 min^?1 throughout. When compared to euglycaemia, hypoglycaemia was associated with: (1) increment in circulating glucagon (65 ± 8 vs 23 ± 4 ng l^?1, p < 0.05), growth hormone (19.9 ± 3.6 vs 2.6 ± 1.3 μg l^?1, p < 0.05), adrenaline (410 ± 88 vs 126 ± 32 ng l^?1, p < 0.05) and increased suppression of C-peptide (0.5 ± 0.1 vs 1.0 ± 0.1 μg l^?1, p < 0.05) along with a modest lowering of insulin (103 ± 10 vs 130 ± 13 mU l^?1, p < 0.05); (b) decrease in plasma glucose level (3.0 ± 0.07 vs 5.0 ± 0.12 mmol l^?1 p < 0.05), forearm glucose uptake (0.21 ± 0.09 vs 1.21 ± 0.21 mmol l^?1, p < 0.05) and requirement for exogenous glucose (5.6 ± 1.1 vs 13.2 ± 0.9 mg kg^?1 min^?1 p < 0.005) together with an impaired suppression of isotopically determined endogenous glucose production (0.34 ± 0.5 vs ?2.3 ± 0.3 mg kg^?1 min^?1, p < 0.05); (3) exaggerated increase in blood lactate (1680 ± 171 vs 1315 ± 108 μmol l^?1, p < 0.05) and a decrease in alanine (215 ± 18 vs 262 ± 19 μmol l^?1, p < 0.05). Forearm release of lactate (130 ± 43 vs 12 ± 31 μmol l^?1, p = 0.09) tended to be increased, whereas alanine balance (18 ± 6 vs 17 ± 5 μmol l^?1) was unchanged. (4) Total forearm blood flow increased similarly during both studies (4.4 ± 0.6 vs 4.2 ± 0.5 ml 100 ml^?1 min^?1). These data suggest that the human forearm is not a major site for glucose uptake nor for lactate production during protracted hypoglycaemia; the fact that forearm glucose uptake is reduced sixfold during hypoglycaemia further suggests that restriction of glucose uptake in muscles plays a frontline role in the defence against hypoglycaemia.     

The lipoprotein lipase activator, NO-1886, suppresses fat accumulation and insulin resistance in rats fed a high-fat diet

Abstract Aims/hypothesis. Fat balance is critical in the aetiology of obesity and related diseases. Lipoprotein lipase is of major importance in lipid metabolism. The aim of this study was to investigate the long-term effects of the lipoprotein lipase activator, NO-1886, on substrate utilisation, adiposity and insulin action in rats fed a high-fat diet.?Methods. Male, Sprague-Dawley rats were fed for 10 weeks on a chow diet or a high-fat diet with, or without, NO-1886 (50 mg · kg^–1· day^–1). Weight gain, fat accumulation and both hormone-sensitive and lipoprotein, lipase activities were measured. Insulin action was assessed by the euglycaemic hyperinsulinaemic clamp and metabolic rate/substrate utilisation by open-circuit respirometry.?Results. Compared with chow-fed controls, a high-fat diet increased weight gain, an effect lessened by NO-1886 [weight gain (g): chow, 37 ± 3, high-fat, 222 ± 9; high-fat + NO-1886, 109 ± 6, all groups differed p < 0.001]. A similar pattern existed for fat accumulation [visceral fat (g): chow, 35.9 ± 3.2; high-fat, 81.9 ± 6.6; high-fat + NO-1886, 52.3 ± 4.7, p < 0.01 high-fat vs the other groups]. A high-fat diet induced whole-body insulin resistance (clamp glucose infusion rate: 4.8 ± 1.3 mg · kg^–1· min^–1 vs 10.6 ± 1.1 for the chow group, p < 0.01) with NO-1886 lessening this effect (8.3 ± 0.5, p < 0.05 vs high-fat). The 24-h respiratory quotient was lower in the high-fat + NO-1886 group (0.825 ± 0.010) compared with high-fat alone (0.849 ± 0.004, p < 0.05). A high-fat diet increased lipoprotein and hormone-sensitive, lipase activities in epididymal fat, an effect not altered by NO-1886. In myocardium and skeletal muscle a high-fat diet lowered lipoprotein lipase activity, an effect lessened by NO-1886.?Conclusion/interpretation: Lipoprotein lipase activators could have potential benefits for the treatment of obesity by increasing fat utilisation. [Diabetologia (2000) 43: 875–880] Received: 11 January 2000 and in final revised form: 4 April 2000     

Hyperlipidaemia is associated with increased insulin-mediated glucose metabolism, reduced fatty acid metabolism and normal blood pressure in transgenic mice overexpressing human apolipoprotein C1

Aims/hypothesis. Insulin resistance for glucose metabolism is associated with hyperlipidaemia and high blood pressure. In this study we investigated the effect of primary hyperlipidaemia on basal and insulin-mediated glucose and on non-esterified fatty acid (NEFA) metabolism and mean arterial pressure in hyperlipidaemic transgenic mice overexpressing apolipoprotein C1 (APOC1). Previous studies have shown that APOC1 transgenic mice develop hyperlipidaemia primarily because of an impaired hepatic uptake of very low density lipoprotein (VLDL). Methods. Basal and hyperinsulinaemic (6 mU · kg^–1· min^–1), euglycaemic (7 mmol/l) clamps with 3-³H-glucose or 9,10-³H-palmitic acid infusions and in situ freeze clamped tissue collection were carried out. Results. The APOC1 mice showed increased basal plasma cholesterol, triglyceride, NEFA and decreased glucose concentrations compared with wild-type mice (7.0 ± 1.2 vs 1.6 ± 0.1, 9.1 ± 2.3 vs 0.6 ± 0.1, 1.9 ± 0.2 vs 0.9 ± 0.1 and 7.0 ± 1.0 vs 10.0 ± 1.1 mmol/l, respectively, p < 0.05). Basal whole body glucose clearance was increased twofold in APOC1 mice compared with wild-type mice (18 ± 2 vs 10 ± 1 ml · kg^–1· min^–1, p < 0.05). Insulin-mediated whole body glucose uptake, glycolysis (generation of ³H₂O) and glucose storage increased in APOC1 mice compared with wild-type mice (339 ± 28 vs 200 ± 11; 183 ± 39 vs 128 ± 17 and 156 ± 44 vs 72 ± 17 μmol · kg^–1· min^–1, p < 0.05, respectively), corresponding with a twofold to threefold increase in skeletal muscle glycogenesis and de novo lipogenesis from 3-³H-glucose in skeletal muscle and adipose tissue (p < 0.05). Basal whole body NEFA clearance was decreased threefold in APOC1 mice compared with wild-type mice (98 ± 21 vs 314 ± 88 ml · kg^–1· min^–1, p < 0.05). Insulin-mediated whole body NEFA uptake, NEFA oxidation (generation of ³H₂O) and NEFA storage were lower in APOC1 mice than in wild-type mice (15 ± 3 vs 33 ± 6; 3 ± 2 vs 11 ± 4 and 12 ± 2 vs 22 ± 4 μmol · kg^–1· min^–1, p < 0.05) in the face of higher plasma NEFA concentrations (1.3 ± 0.3 vs 0.5 ± 0.1 mmol/l, p < 0.05), respectively. Mean arterial pressure and heart rate were similar in APOC1 vs wild-type mice (82 ± 4 vs 85 ± 3 mm Hg and 459 ± 14 vs 484 ± 11 beats · min^–1). Conclusions/interpretation. 1) Hyperlipidaemic APOC1 mice show reduced NEFA and increased glucose metabolism under both basal and insulin-mediated conditions, suggesting an intrinsic defect in NEFA metabolism. Primary hyperlipidaemia alone in APOC1 mice does not lead to insulin resistance for glucose metabolism and high blood pressure. [Diabetologia (2001) 44: 437–443] Received: 14 September 2000 and in revised form: 23 November 2000     

Serum Insulin Level Versus Blood Pressure: A Cross-sectional,Case-controlled Study in Non-obese,Middleaged Japanese Subjects with Normal Glucose Tolerance

To assess the relationship between blood pressure (BP) and serum insulin level in nonobese (body mass index (BMI) ≤ 27 kg m^?2), middle-aged (40–64 years of age) Japanese subjects with normal glucose tolerance, a three-phase study protocol was designed. First, the responses of plasma glucose and serum insulin to an oral glucose load were compared between 40 patients with untreated essential hypertension and 40 age-, sex- and BMI-matched normotensive control subjects. Second, the glucose and insulin responses to an i.v. glucose load were evaluated in 7 non-obese hypertensive, 7 non-obese normotensive and 7 obese hypertensive subjects. Third, BP and serum lipid profile were compared between 21 hyperinsulinaemic (serum insulin level (while fasting, after glucose loading, or both) > 2 SDs higher than the mean) and 21 age-, sex- and BMI-matched normoinsulinaemic subjects (serum insulin level within 1 SD of the mean). The glucose and insulin responses to the oral glucose load were comparable between the hypertensive and normotensive groups. Similarly, the glucose and insulin responses to the i.v. glucose load were comparable between the non-obese hypertensive and normotensive groups, whereas the mean AUC_insulin in the obese hypertensive group was significantly greater (p < 0.01) than that in either of the non-obese groups. The respective mean values for systolic and diastolic BPs did not differ between the hyperinsulinaemic and normoinsulinaemic groups. The mean serum triglyceride and HDL cholesterol concentrations were significantly higher (p < 0.01) and lower (p < 0.05), respectively, in the hyperinsuslinaemic than in the normoinsulinaemic group. The results suggest no association between serum insulin level and BP in non-obese, middle-aged, Japanese subjects with normal glucose tolerance.     

Serum lipoprotein lipid profile in women with the polycystic ovary syndrome: relation to anthropometric, endocrine and metabolic variables

OBJECTIVE Although often associated with insulin resistance and glucose intolerance, various lipoprotein abnormalities have been found in polycystic ovary syndrome (PCOS) but not Invariably so when the degree of obesity is taken into account. We have therefore Investigated the serum lipid profile in a group of women with polycystic ovary syndrome with and without obesity. DESIGN Cross-sectional study of serum lipoprotein lipids and plasma free fatty acids in relation to anthropometric, metabolic and hormonal variables in women with PCOS and weight-matched controls. PATIENTS Twenty-four obese (Pob, mean BMI ± SD 30·6±3·3kg/m²) and 25 non-obese (Pnob, 22·2 ±2·3kg/m²) women with PCOS. Twenty obese (Cob, 30·2 ± 3·5 kg/m²) and 20 non-obese (Cnob, 21·4 ± 1·5 kg/m²) controls. MEASUREMENTS Fasting concentrations of plasma free fatty acids, serum cholesterol and triglycerides in high density lipoproteins (HDL), low density lipoproteins (LDL) and very low density lipoproteins (VLDL) In relation to insulin sensitivity index (M/I; assessed with the euglycaemic insulin clamp), glucose tolerance (k-value; intravenous glucose tolerance test), basal serum hormone concentrations, and body fat distribution (skinfolds and waist hip ratio). RESULTS Plasma concentrations of free fatty acids were markedly higher in Pob than in the other groups (all P < 0 001). The lipoprotein lipids did not differ between Pob and Cob, or between the non-obese groups, whereas both obese groups had higher serum concentrations of triglycerides, totally and in VLDL, and lower HDL-cholesterol than their non-obese counterparts. Pob also had higher serum levels of total and LDL-cholesterol than Pnob. Pob had a more pronounced subcutaneous truncal-abdominal adiposity, higher fasting insulin levels and lower M/I than the other groups, and a lower k-value than Cob. Cob had higher levels of fasting insulin than Cnob. Free fatty acid levels correlated with the k-value (inversely) in both women with PCOS and controls, and with M/I (inversely), age and testosterone levels in PCOS. Step-wise regression analysis for the total population, comparing endocrine, anthropometric and metabolic explanatory variables, showed that the serum levels of HDL-cholesterol and triglycerides were mainly correlated with body fat distribution (both) and fasting insulin levels (triglycerides), and levels of total and LDL-cholesterol with BMI and age. CONCLUSIONS Plasma free fatty acid correlations were markedly increased In obese women with PCOS, closely associated with the lower insulin sensitivity and lower glucose tolerance in these women. In spite of these profound metabolic aberrations, the lipoprotein lipid profile was not significantly more abnormal in obese women with PCOS than in their weight-matched controls.     

Intramuscular triglyceride content is increased in IDDM

Summary Increased lipid oxidation is related to insulin resistance. Some of the enhanced lipid utilization may be derived from intramuscular sources. We studied muscle triglyceride (mTG) concentration and its relationship to insulin sensitivity in 10 healthy men (age 29 ± 2 years, BMI 23.3 ± 0.6 kg/m²) and 17 men with insulin-dependent diabetes mellitus (IDDM) (age 30 ± 2 years, BMI 22.8 ± 0.5 kg/m², diabetes duration 14 ± 2 years, HbA_{1 c} 7.7 ± 0.3 %, insulin dose 48 ± 3 U/day). Insulin sensitivity was measured with a 4 h euglycaemic (5 mmol/l) hyperinsulinaemic (1.5 mU or 9 pmol · kg^–1· min^–1) clamp accompanied by indirect calorimetry before and at the end of the insulin infusion. A percutaneous biopsy was performed from m. vastus lateralis for the determination of mTG. At baseline the IDDM patients had higher glucose (10.2 ± 0.9 vs 5.6 ± 0.1 mmol/l, p < 0.001), insulin (40.3 ± 3.2 vs 23.2 ± 4.2 pmol/l, p < 0.01), HDL cholesterol (1.28 ± 0.06 vs 1.04 ± 0.03 mmol/l, p < 0.01) and mTG (32.9 ± 4.6 vs 13.6 ± 2.7 mmol/kg dry weight, p < 0.01) concentrations than the healthy men, respectively. The IDDM patients had lower insulin stimulated whole body total (–25 %, p < 0.001), oxidative (–18 %, p < 0.01) and non-oxidative glucose disposal rates (–43 %, p < 0.001), whereas lipid oxidation rate was higher in the basal state ( + 44 %, p < 0.01) and during hyperinsulinaemia ( + 283 %, p < 0.05). mTG concentrations did not change significantly during the clamp or correlate with insulin stimulated glucose disposal. In healthy men mTG correlated positively with lipid oxidation rate at the end of hyperinsulinaemia (r = 0.75, p < 0.05). In conclusion: 1) IDDM is associated with increased intramuscular TG content. 2) mTG content does not correlate with insulin sensitivity in healthy subjects or patients with IDDM. [Diabetologia (1998) 41: 111–115] Received: 12 June 1997 and in revised form: 8 September 1997     

Co-existence of severe insulin resistance and hyperinsulinaemia in pre-adolescent obese children

Summary To determine the time course of changes in insulin action and secretion that occur early during the development of obesity, we studied children before the onset of puberty. The reason for choosing the prepubertal stage of development is that it is metabolically characterized by both a high sensitivity to insulin and low glucose stimulated insulin responses. Fifteen obese preadolescents (8 male/7 female, age 10 ± 0.4 years, body mass index (BMI) 31 ± 1.2 kg/m² Tanner Stage I) with a duration of obesity of less than 5 years and 10 non-obese preadolescents (6 male/4 female, age 10 ± 0.4 years, BMI 18 ± 0.9 kg/m²) matched for gender were studied. In a cross-sectional analysis, we compared responses in obese preadolescents, with those in obese adolescents and obese adults with a longer duration of obesity. The euglycaemic hyperinsulinaemic clamp with 1-¹³C-glucose (Hot Ginf) and indirect calorimetry were used to quantitate insulin action and the hyperglycaemic clamp used to assess beta-cell function. Insulin-stimulated glucose uptake measured at two physiological levels of hyperinsulinaemia ( ∼ 180 and 480 pmol) was reduced by 20 and 45 % in all three groups of obese compared to non-obese subjects (p < 0.01). Defects in oxidative and non-oxidative glucose metabolism were observed in all three groups of obese subjects at the higher insulin infusion rate. The ability of insulin to inhibit lipid oxidation was impaired in all three obese groups at both levels of hyperinsulinaemia. Increases in basal and glucose-stimulated insulin levels during the hyperglycaemic clamp mirrored the reductions in glucose uptake during the insulin clamp in all obese groups. These results indicate that insulin resistance and hyperinsulinaemia co-exist in preadolescent children with moderate to severe obesity. [Diabetologia (1996) 39: 1489–1497] Received: 23 March 1996 and in revised form: 16 July 1996     

No deterioration in insulin sensitivity,but impairment of both pancreatic β-cell function and glucose sensitivity,in Japanese women with former gestational diabetes mellitus

To identify the primary pathogenic factors involved in the development of Type 2 diabetes mellitus (DM), we studied Japanese women with former gestational diabetes mellitus (GDM) who are at risk for the later development of Type 2 DM. We used the minimal model analysis derived from frequently sampled intravenous glucose tolerance test (FSIGT). The subjects consisted of eight non-obese women with a history of GDM and eight non-obese normal women as control subjects. The 75 g oral glucose tolerance test (75 g OGTT) performed within 6 months of delivery confirmed that all the subjects with former GDM had a normal glucose tolerance. Insulin sensitivity (SI) derived from the minimal model analysis was not different between the two groups. Glucose effectiveness at zero insulin (GEZI), reflecting tissue glucose sensitivity, was significantly lower in former GDM patients than in control subjects (1.18 ± 0.34 vs 2.26 ± 0.29 × 10⁻² min⁻¹, p < 0.05). The early phase insulin secretion found in FSIGT was markedly reduced to 56 % of that observed in control subjects (1250 ± 187.4 vs 2223 ± 304.3 pmol l⁻¹ min, p < 0.01). Our results indicate that in former GDM patients, who are Japanese and non-obese, impairment of the acute insulin response to glucose and a decrease in tissue glucose sensitivity rather than insulin sensitivity are the primary pathogenic factors involved. Copyright © 1998 John Wiley & Sons, Ltd.     

Lack of acute effect of amylin (islet associated polypeptide) on insulin sensitivity during hyperinsulinaemic euglycaemic clamp in humans

Summary It is suggested that amylin (islet associated polypeptide), co-secreted with insulin from the pancreatic beta cells acts as a circulating hormone which opposes the action of insulin on muscle and increases hepatic glucose production. We have tested the effect of amylin in human subjects on postabsorptive glucose homeostasis and on insulin sensitivity using the euglycaemic hyperinsulinaemic clamp. The amylin used opposed insulin-mediated glucose disposal in rat soleus muscle at concentrations of 10 nmol/l. Seven subjects were studied on two occasions and infused with either amylin or placebo for 6 h, initially when postabsorptive and then during a euglycaemic hyperinsulinaemic clamp. Mean plasma amylin concentrations during the first 3 h were 2006±327 pmol/l during amylin infusion and 20±9 pmol/l during the control infusion. Amylin infusion had no effect on postabsorptive plasma concentrations of insulin (control: 32±16 vs amylin: 25±8 pmol/l) or glucose (5.1±0.1 vs 5.3±0.1 mmol/l). During the clamp, amylin concentrations were 1636 ±422 pmol/l when it was infused and 24±6 during control infusions. Plasma glucose and insulin concentrations were well matched during the control and amylin infusions (glucose: 4.7±0.1 vs 4.8±0.1 mmol/l; insulin: 198±37 vs 195±22 pmol/l). Exogenous glucose infusion rates were a mean of 13 % lower than control values during the amylin infusion but were not statistically different (p =0.17). Therefore, an approximately 100-fold elevation of plasma amylin concentration failed to consistently alter glucose metabolism. Our data suggest that amylin does not act as a circulating hormone to influence glucose metabolism in humans. [Diabetologia (1994) 37: 166–169] Received: 1 June 1993 and in revised form: 16 August 1993     

Plasminogen Activator Inhibitor (PAI-1) Activity is Elevated in Asian and Caucasian Subjects with Non-insulin-dependent (Type 2) Diabetes but not in Those with Impaired Glucose Tolerance (IGT) or Non-diabetic Asians

In order to study the plasminogen activator inhibitor activity (PAI-1) in subjects at different risk of non-insulin-dependent diabetes and ischaemic heart disease we examined 89 subjects with diet controlled NIDDM (49 Caucasian, 40 Asian), 29 with impaired glucose tolerance (IGT) (13 Caucasian, 16 Asian), and 149 with normal glucose tolerance (67 Caucasian, 82 Asian). Diabetes was diagnosed by WHO criteria and highly specific, monoclonal antibody-based assays were used to measure insulin, intact proinsulin, and des 31,32 proinsulin. Subjects with NIDDM were significantly more obese, had more central distribution of obesity, higher fasting plasma specific insulin concentrations (NIDDM median 74 pmol l⁻¹ vs IGT 41 pmol l⁻¹, p < 0.01 and vs normals 34 pmol l⁻¹, p < 0.001) and higher PAI-1 activity than normals and those with IGT (NIDDM 23.0 ± 6.9 vs IGT 16.8 ± 5.0, p < 0.001 and vs normals 17.1 ± 6.9 AU ml⁻¹, p < 0.001). However, PAI-1 activity was not significantly different between Asian and Caucasian normals (17.5 ± 7.3 vs 16.5 ± 6.4 AU ml⁻¹, p = ns) and diabetic (22.8 ± 7.3 vs 23.1 ± 6.6 AU ml⁻¹, p = ns) subjects. In addition to relationships with obesity and plasma triglyceride, PAI-1 activity, after controlling for age, sex, body mass index, and waist–hip ratio, was related to fasting insulin (partial r = 0.22, p < 0.001), intact proinsulin (partial r = 0.36, p < 0.001), and des 31,32 proinsulin concentrations (partial r = 0.33, p < 0.001) as measured by highly specific assays. The association of PAI-1 with diabetes was weakened but remained statistically significant (p = 0.042) after controlling for age, sex, ethnicity, obesity, plasma triglyceride, and all insulin-like molecules. We conclude that, although PAI-1 activity is raised in subjects with diet-treated NIDDM, it is normal in subjects with IGT and non-diabetic Asians, populations at high risk of NIDDM and ischaemic heart disease. Raised PAI-1 activity may play an important role in the pathogenesis of macrovascular disease in subjects with NIDDM, but is unlikely to explain excess risk of ischaemic heart disease in Asians and those with impaired glucose tolerance.     

Oral magnesium supplementation in insulin-requiring Type 2 diabetic patients

Oral magnesium (Mg) supplementation can improve insulin sensitivity and secretion in patients with Type 2 diabetes mellitus (DM). We studied the effect of Mg supplementation on glycaemic control, blood pressure, and plasma lipids in insulin-requiring patients with Type 2 DM. Fifty moderately controlled patients were randomized to 15 mmol Mg or placebo daily for 3 months. Plasma Mg, glucose, HbA_1c, lipids, erythrocyte Mg, Mg and glucose concentrations in 24-h urine, and systolic and diastolic pressure were measured before and after 3 months treatment. Plasma Mg concentration was higher after supplementation than after placebo (0.82 ± 0.07 vs 0.78 ± 0.08 mmol l⁻¹, p<0.05), as was Mg excretion (5.5 ± 1.9 vs 3.7 ± 1.4 mmol 24 h⁻¹, p = 0.004) but erythrocyte Mg concentrations were similar. No significant differences were found in glycaemic control (glucose: 10.7 ± 3.8 vs 11.6 ± 6.2 mmol l⁻¹, p = 0.8; HbA_1c: 8.9 ± 1.6 vs 9.1 ± 1.2%, p = 0.8), lipids or blood pressure. On-treatment analysis (34 patients: 18 on Mg, 16 on placebo) yielded similar results. An increase in plasma Mg concentration irrespective of medication was associated with a tendency to a decrease in diastolic pressure (increased plasma Mg vs no increase: −4.0 ± 10.1 vs +2.5 ± 12.0 mmHg, p = 0.059). Three months’ oral Mg supplementation of insulin-requiring patients with Type 2 DM increased plasma Mg concentration and urinary Mg excretion but had no effect on glycaemic control or plasma lipid concentrations. © 1998 John Wiley & Sons, Ltd.     

The Effect of Spironolactone on Lipid,Glucose and Uric Acid Levels in Blood during Long-Term Administration to Hypertensives

Spironolactone, an aldosterone antagonist, was given in a daily dose of 100 mg to 15 patients with primary hypertension for one year. Fasting levels of lipids, uric acid, glucose, insulin, potassium and growth hormone were measured before and after 6 and 12 months of treatment. Total cholesterol, LDL cholesterol, glucose, potassium and growth hormone were unchanged, HDL cholesterol fell from (mean±SD) 1.5±0.6 to 1.1 ±0.3 mmol/l (p<0.05) after 6 months of treatment and remained lowered (1.0 ±0.3 mmol/l) (p<0.01) after 12 months of treatment. There was a transient fall after 6 months of treatment in triglycerides from 2.4±1.5 to 2.0±1.1 mmol/l (p < 0.05), uric acid from 380±73 to 342±58 μmol/l (p<0.05) and an increase in insulin from 16±9.5 to 28.6±26.8 mU/l (p<0.05). The blood glucose curves above fasting levels after glucose loading were unchanged during spironolactone treatment, whereas the area under the net insulin curve was higher after 6 months of treatment (163±103 mU · h/l) than before treatment (105±71 mU·h/l), indicating a small and transient insulin resistance. Thus, spironolactone impaired the glucose tolerance transiently and gave small and almost transient changes in fasting serum lipid and uric acid levels.     

Improved Blood Glucose Control by Insulin Therapy in Type 2 Diabetic Patients Has No Effect on Lipoprotein(a) Levels

The effects of improved blood glucose control by insulin therapy on lipoprotein(a) and other lipoproteins were studied in 54 patients with Type 2 diabetes (mean ± SD: age 67 ± 9 years, body mass index 26.1 ± 4.4 kg m^?2, median duration of diabetes 10 (range 1–37) years, 23 males, 31 females), who were poorly controlled despite diet and maximal doses of oral hypoglycaemic agents. After 6 months of insulin treatment, mean fasting blood glucose concentrations had decreased from 14.1 ± 2.2 mmol l^?1 to 8.4 ± 1.8 mmol l^?1 (p < 0.001), and HbA^1c had fallen from 11.1 ± 1.4 % to 8.2 ± 1.1 % (p < 0.001). Significant decreases of total and LDL cholesterol, triglycerides, apolipoprotein B, and free fatty acids were observed, while HDL-cholesterol and apoA1 increased by 10 %. Baseline serum Lp(a) levels were elevated compared to non-diabetic subjects of similar age (median 283, range 8–3050 mg I^?1, vs 101, range 8–1747 mg I^?1, p < 0.05), but did not change with insulin, and there was no correlation with the degree of metabolic improvement and changes in Lp(a) levels. It is concluded that improved blood glucose control by insulin therapy does not alter elevated Lp(a) levels in Type 2 diabetic patients, but has favourable effects on the other lipoproteins.     

Protracted glucose fall in subcutaneous adipose tissue and skeletal muscle compared with blood during insulin-induced hypoglycaemia

Summary The absolute glucose concentrations in subcutaneous adipose tissue and skeletal muscle were determined with microdialysis in 10 normal-weight, healthy subjects during a standardized hyperinsulinaemic hypoglycaemic clamp. The concentration of tissue dialysate glucose was measured in 15-min fractions and compared with that in arterialized venous plasma. Insulin (0.15 U · kg^-1· h⁻¹) was infused i. v. to lower the plasma glucose level to 2.5 mmol/l over 30 min. This level was maintained for 30 min by using a variable glucose infusion. Thereafter, the insulin infusion was stopped and the plasma glucose level was gradually increased to baseline levels over 120 min. During a 60-min basal period, the glucose levels in muscle were 0.6 mmol/l lower than those in plasma (p = 0.002), whereas the levels in adipose tissue and plasma were similar. The glucose nadirs in muscle (1.6 ± 0.1 mmol/l) and adipose tissue (2.0 ± 0.1 mmol/l) were significantly lower than that in plasma (2.4 ± 0.1 mmol/l) (p = 0.001 and 0.02, respectively), and the time-to-nadir was substantially longer in muscle (69 ± 5 min) and adipose tissue (57 ± 2 min) than in plasma (39 ± 3 min) (p = 0.0004). When the insulin infusion was stopped, the increases in adipose tissue and muscle glucose concentrations were delayed by approximately 25 and 45 min, respectively, as compared to the increase in plasma glucose. Thus, it seems that glucose measurements in adipose tissue and muscle more adequately reflect overall tissue homeostasis than do measurements in blood and that clinically relevant tissue glucopenia may be overlooked by conventional blood glucose measurements. [Diabetologia (1997) 40: 1320–1326] Received: 21 January 1997 and in final revised form: 2 July 1997     

Glucagon secretion in relation to insulin sensitivity in healthy subjects

Aims/hypothesis The study evaluated whether glucagon secretion is regulated by changes in insulin sensitivity under normal conditions. Materials and methods A total of 155 healthy women with NGT (aged 53–70 years) underwent a glucose-dependent arginine-stimulation test for evaluation of glucagon secretion. Arginine (5 g) was injected i.v. under fasting conditions (plasma glucose 4.8±0.1 mmol/l) and after raising blood glucose concentrations to 14.8±0.1 and 29.8±0.2 mmol/l. The acute glucagon response (AGR) to arginine during the three glucose levels (AGR₁, AGR₂, AGR₃) was estimated, as was the suppression of baseline glucagon by the increased glucose. All women also underwent a 2-h euglycaemic–hyperinsulinaemic clamp study for estimation of insulin sensitivity. Results Insulin sensitivity was normally distributed, with a mean of 73.2±29.3 (SD) nmol glucose kg⁻¹ min⁻¹/pmol insulin l⁻¹. When relating the variables obtained from the arginine test to insulin sensitivity, insulin resistance was associated with increased AGR and with increased suppression of glucagon levels by glucose. For example, the regression between insulin sensitivity and AGR₂ was r=−0.38 (p<0.001) and between insulin sensitivity and suppression of glucagon levels by 14.8 mmol/l glucose r=0.36 (p<0.001). Insulin sensitivity also correlated negatively with insulin secretion; multivariate analysis revealed that changes in insulin sensitivity and insulin secretion were independently related to changes in glucagon secretion. Conclusions/interpretation The body adapts to insulin resistance by increasing the glucagon response to arginine and by increasing the suppression of glucagon levels by glucose. Hence, not only the islet beta cells but also the alpha cells seem to undergo compensatory changes during the development of insulin resistance.     

Mechanism of protracted metabolic effects of fatty acid acylated insulin, NN304, in dogs: retention of NN304 by albumin

Aims/hypothesis. The provision of stable, reproducible basal insulin is crucial to diabetes management. This study in dogs examined the metabolic effects and interstitial fluid (ISF) profiles of fatty acid acylated insulin, Lys^B29-tetradecanoyl, des-(B30) human insulin (NN304). Methods. Euglycaemic clamps were carried out under inhalant anaesthesia during equimolar intravenous infusions (3.6 pmol · min^–1· kg^–1 for 480 min) of human insulin or NN304 (n = 8 per group). Results. Steady-state total NN304 (albumin-bound and unbound) was considerably higher in plasma compared with human insulin (1895 ± 127 vs 181 ± 10 pmol/l, p < 0.001) and increased in interstitial fluid (163 ± 14 vs 106 ± 9 pmol/l, p < 0.01). The halftime for appearance of NN304 in interstitial fluid was slower than human insulin (92 vs 29 min, p < 0.001). Yet, equivalency of action was shown for glucose turnover; steady-state glucose uptake (Rd) of 7.28 ± 0.55 and 6.76 ± 0.24 mg · min^–1· kg^–1 and endogenous glucose production of 0.11 ± 0.12 and 0.22 ± 0.03 mg · min^–1· kg^–1 (p > 0.40; NN304 and human insulin, respectively). Similar to interstitial fluid, half times for Rd and endogenous glucose production were delayed during NN304 infusion (162 vs 46 min and 80 vs 31 min, respectively; p < 0.01 vs human insulin). Conclusion/interpretation. Firstly equivalency of steady-state action is found at equimolar physiologic infusions of human insulin and NN304. Secondly NN304 binding to plasma albumin results in slower NN304 appearance in the interstitial compartment compared with human insulin. Thirdly the delay in appearance of NN304 in interstitial fluid may not in itself be a source of the protracted action of this insulin analogue. The protracted effect is due primarily to albumin binding of the insulin analogue NN304. [Diabetologia (1999) 42: 1254–1263] Received: 16 March 1999 and in revised form: 11 May 1999     

Risk and mechanism of dexamethasone-induced deterioration of glucose tolerance in non-diabetic first-degree relatives of NIDDM patients

Summary We tested the hypothesis that glucose intolerance develops in genetically prone subjects when exogenous insulin resistance is induced by dexamethasone (dex) and investigated whether the steroid-induced glucose intolerance is due to impairment of beta-cell function alone and/or insulin resistance. Oral glucose tolerance (OGTT) and intravenous glucose tolerance tests with minimal model analysis were performed before and following 5 days of dex treatment (4 mg/day) in 20 relatives of non-insulin-dependent diabetic (NIDDM) patients and in 20 matched control subjects (age: 29.6 ± 1.7 vs 29.6 ± 1.6 years, BMI: 25.1 ± 1.0 vs 25.1 ± 0.9 kg/m²). Before dex, glucose tolerance was similar in both groups (2-h plasma glucose concentration (PG): 5.5 ± 0.2 [range: 3.2–7.0] vs 5.5 ± 0.2 [3.7–7.4] mmol/l). Although insulin sensitivity (Si) was significantly lower in the relatives before dex, insulin sensitivity was reduced to a similar level during dex in both the relatives and control subjects (0.30 ± 0.04 vs 0.34 ± 0.04 10^–4 min^–1 per pmol/l, NS). During dex, the variation in the OGTT 2-h PG was greater in the relatives (8.5 ± 0.7 [3.9–17.0] vs 7.5 ± 0.3 [5.7–9.8] mmol/l, F-test p < 0.05) which, by inspection of the data, was caused by seven relatives with a higher PG than the maximal value seen in the control subjects (9.8 mmol/l). These “hyperglycaemic” relatives had diminished first phase insulin secretion (?1) both before and during dex compared with the “normal” relatives and the control subjects (pre-dex ?1: 12.6 ± 3.6 vs 26.4 ± 4.2 and 24.6 ± 3.6 (p < 0.05), post-dex ?1: 22.2 ± 6.6 vs 48.0 ± 7.2 and 46.2 ± 6.6 respectively (p < 0.05) pmol · l^–1· min^–1 per mg/dl). However, Si was similar in “hyperglycaemic” and “normal” relatives before dex (0.65 ± 0.10 vs 0.54 ± 0.10 10−4 · min^–1 per pmol/l) and suppressed similarly during dex (0.30 ± 0.07 vs 0.30 ± 0.06 10−4 · min^–1 per pmol/l). Multiple regression analysis confirmed the unique importance of low pre-dex beta-cell function to subsequent development of high 2-h post-dex OGTT plasma glucose levels (R ² = 0.56). In conclusion, exogenous induced insulin resistance by dex will induce impaired or diabetic glucose tolerance in those genetic relatives of NIDDM patients who have impaired beta-cell function (retrospectively) prior to dex exposure. These subjects are therefore unable to enhance their beta-cell response in order to match the dex-induced insulin resistant state. [Diabetologia (1997) 40: 1439–1448] Received: 20 January 1997 and in final revised form: 17 July 1997     

Insulin Secretion and Sensitivity in Women Fulfilling WHO Criteria for Gestational Diabetes

Abnormalities of insulin secretion rather than insulin sensitivity are described in women fulfilling the American criteria for gestational diabetes. We examined insulin secretion and insulin sensitivity in 38 women at risk of gestational diabetes categorized according to the less stringent WHO criteria, based on the 75 g oral glucose tolerance test, performed at 24 weeks gestation. Insulin sensitivity was assessed at 28 and 36 weeks using the short insulin tolerance test. Applying WHO criteria, 18 women had GDM. Age and body mass index of the GDM and glucose tolerant women were similar (32.4 ± 1.1 (SE) vs 32.3 ± 1.9 yr; 28.7 ± 1.5 vs 28.8 ± 1.7 kg m^-2, respectively). Fasting glucose was higher in the GDM women than controls (5.1 ± 0.2 vs 4.5 ± 0.1 mmol l^-1, p<0.025) while fasting insulin was similar (75 ± 18 vs 90 ± 16 pmol l^-1). The 30-min insulin concentration during the OGTT was lower in the GDM women than controls (436 ± 61 vs 788 ± 152 pmol l^-1, p< 0.05), while the insulin sensitivity at 28 (87 ± 5 vs 76 ± 5 μmol l^-1 min) and 36 weeks (73 ± 8 vs 76 ± 8 μmol l^-1 min) was similar. A negative correlation existed between the 30-min insulin and 120-min glucose concentration during the OGTT (Rho -0.328, p<0.05). The WHO criteria for GDM identify women with similar abnormalities of insulin secretion as the more stringent American criteria.