Non-insulin-dependent Diabetes Mellitus Subjects Research Articles

Dietary protein restriction alters glucose but not protein metabolism in non—insulin-dependent diabetes mellitus

We determine whether a customary diet high or low in protein (1) influences postabsorptive amino acid catabolism, nitrogen (N) balance, and hepatic glucose output (HGO) in normal subjects or patients with non—insulin-dependent diabetes mellitus (NIDDM) or (2) alters blood glucose levels in NIDDM. Eight normal young adults and five obese middle-aged persons with NIDDM consumed low-protein (0.8 g/kg lean body mass [LBM]) or high-protein (3.0 g/kg LBM) diets at maintenance energy for consecutive 7-day periods. Fasting and average blood glucose and N balance were measured daily. The level of dietary protein had no effect on the basal plasma leucine rate of appearance (Ra) or urinary 3-methylhistidine excretion in either subject group. Basal leucine oxidation (and by inference, whole-body amino acid catabolism) was reduced on the low-protein diet but basal HGO was not, and although exogenous glucose effectively suppressed HGO, it did not reduce leucine oxidation with either diet. After adaptation to the low-protin diet, N balance in both the normal and NIDDM subjects was close to zero. The low-protein diet reduced the fasting and daily blood glucose of the diabetic subjects by approximately 2 mmol/L ( P < .05). We conclude that physiologic variation in dietary protein does not affect basal whole-body protein turnover or HGD in either normal young adults or obese middle-aged NIDDM subjects. However, protein restriction to the level of the average daily requirement significantly reduces postabsorptive and average daily blood glucose concentrations in persons with NIDDM.

Hormonal status and NIDDM in the European and Melanesian populations of New Caledonia: a case-control study. The CALedonia DIAbetes Mellitus (CALDIA) Study Group.

To assess ethnic differences in androgenic status related to non insulin-dependent diabetes mellitus (NIDDM) in male and female Melanesians and Europeans of New Caledonia. This is a case-control study nested in a prevalence study for diabetes mellitus in the multiracial population of New Caledonia. 186 male subjects were included in the survey (77 Melanesians and 16 Europeans in each case and control group). Each case and control group included 104 female Melanesian subjects (69 premenopausal and 35 postmenopausal). Diabetic subjects were matched for age, gender, ethnic group and location, with healthy normoglycaemic subjects. Testosterone levels in men and sex hormone-binding globulin (SHBG) levels in women (measured by radioimmunoassay, RIA) were compared between NIDDM and control subjects in relation to obesity, central adiposity and insulin levels. In both ethnic groups, NIDDM was associated with lower testosterone levels but there was a marked difference among Europeans. Testosterone was negatively associated with the body mass index (BMI) (r= -0.35, P <0.01) and fasting insulin (r= -0.37, P <0.001) in control Melanesians only. In Melanesian women, NIDDM was associated with lower SHBG levels in pre- and postmenopausal women (P <0.001). SHBG mean level was not associated with menopausal status. Our results confirm in a Pacific population that NIDDM is associated with low levels of testosterone in men and low levels in SHBG in women. In contrast to white populations, Melanesian women have a more androgenic profile, whatever their menopausal status.

Overt albuminuria predicts diabetic retinopathy in Hispanics with NIDDM

Non-insulin-dependent diabetes mellitus (NIDDM) occurs with a higher frequency in Hispanic as compared with non-Hispanic whites. It also appears that there is a higher prevalence of diabetic nephropathy in the Hispanic population when compared with non-Hispanic whites. In the current study, 144 Hispanics and 671 non-Hispanic white NIDDM subjects were studied to determine the possible association of various risk factors and diabetic complications, including overt albuminuria, with diabetic retinopathy. Stereoscopic retinal fundus photographs were obtained and graded by the University of Wisconsin Fundus Photographic Reading Center. We also sought to determine whether risk factors for retinopathy vary between Hispanics and non-Hispanic whites. In the total group, duration of diabetes, glycosylated hemoglobin, neuropathy, diastolic hypertension, use of insulin, and Hispanic ethnicity correlated with the presence of retinopathy. Controlling for severity and duration of diabetes, Hispanics had a significantly increased risk of retinopathy relative to non-Hispanic whites (OR = 2.13, 95% CI = 1.34, 3.37, P = 0.0013). Duration of diabetes and presence of neuropathy were significantly correlated with the presence of diabetic retinopathy in Hispanics and non-Hispanic whites. The presence of overt albuminuria (>200 microg/min), although not related to diabetic retinopathy in non-Hispanic whites, conferred a high risk for diabetic retinopathy in Hispanics (OR = 11.14, CI = 1.20, 103.39, P = 0.0339) independent of other risk factors. In summary, Hispanics with NIDDM have an increased prevalence of diabetic retinopathy when compared with non-Hispanic whites. In addition, overt albuminuria in the Hispanic subjects appears to be a powerful predictor of the diabetic retinopathy. (Am J Kidney Dis 1998 Jun;31(6):947-53)

Plasma homocysteine concentrations are regulated by acute hyperinsulinemia in nondiabetic but not type 2 diabetic subjects

An association between hyperhomocysteinemia and premature atherosclerosis in patients with non—insulin-dependent diabetes mellitus (NIDDM) has recently been described. Little is known about the role of insulin in homocysteine [H(e)] metabolism. We measured plasma H(e) concentrations in the fasting state and during a hyperinsulinemic-euglycemic clamp in normal subjects and patients with NIDDM. Plasma H(e) decreased significantly from 7.2 ± 2.6 to 6.0 ± 2.7 mmol/L ( P < .01) in normal subjects, but did not change in patients with NIDDM (6.0 ± 2.7 to 5.9 ± 2.5 mmol/L, respectively). These data suggest that plasma H(e) concentrations are regulated by acute hyperinsulinemia in normal subjects, but not in insulin-resistant NIDDM subjects. These abnormalities may have implications for the pathogenesis of premature vascular disease associated with NIDDM.

Effect of insulin versus sulfonylurea therapy on cardiovascular risk factors and fibrinolysis in type II diabetes

In non—insulin-dependent diabetes mellitus (NIDDM), cardiovascular risk factors improve during treatment, but whether insulin (I) differs from sulfonylurea (SU) therapy is unclear. To separate the contributions of improved diabetic control versus treatment regimen to risk factors, we examined the effects of SU and I on insulin sensitivity, basal and post—glucose load levels of insulin-like molecules, fibrinolysis, and lipid concentrations. Twenty poorly controlled, diet-treated NIDDM subjects were given I or SU each for a period of 16 weeks in a randomized crossover study, with a 4-week washout period between each treatment. Subjects were studied at the baselines (B1 and B2) and after each treatment. Treatment with I or SU produced similar improvements in glycemia (hemoglobin A 1 [HbA 1] B1, 11.7% ± 2.1%; SU, 8.5% ± 0.9%; I, 8.6% ± 1.2%) and the metabolic clearance rate of glucose ([MCR-G] B1, 1.86 ×/÷ 1.4; SU, 2.36 ×/÷ 1.4 ( P = .005 v B1); I, 2.27 ×/÷ 1.4 ( P = .07 v B1) ml · kg −1 · min −1). On SU therapy, subjects had higher fasting and post—glucose load levels of intact proinsulin compared with B1 and I (fasting, 13.9 ×/÷ 2.6 v 9.5 ×/÷ 2.2 ( P = .004) and 9.1 ×/÷ 2.4 pmol · L −1 ( P = .01), respectively). Plasminogen activator inhibitor-1 (PAI-1) activity and antigen were higher than at B1 on SU therapy (23.7 v 19.9 AU · mL −1 ( P = .02) and 47.6 v 32.2 ng · mL −1 ( P = .006), respectively), but not on I. There were no changes compared with B1 and no differences between the two therapies in total, very—low-density lipoprotein (VLDL), and intermediate-density lipoprotein (IDL) cholesterol and triglyceride, low-density lipoprotein (LDL), high-density lipoprotein 2 (HDL 2) and HDL 3 cholesterol, apolipoprotein (apo) A1, A2, and B1, or lipoprotein (a) [Lp(a)] levels. In conclusion, (1) treatment with SU or I resulted in equal improvement in glycemia and insulin sensitivity, (2) intact proinsulin and PAI-1 antigen and activity were higher on SU, and (3) there were no differences in lipid concentrations with improved glycemia or between therapies.

High frequency of polymorphism but no mutations found in the GLUT1 glucose transporter gene in NIDDM and familial obesity by SSCP analysis.

To evaluate whether a structural defect in the human glucose transporter gene GLUT1 could be involved in the aetiology of insulin resistance, a key factor of non-insulin-dependent diabetes mellitus (NIDDM) and obesity, we performed single-strand conformation polymorphism (SSCP) analysis in 40 subjects (20 NIDDM patients and 20 subjects with familial obesity). The GLUT1 gene, which is involved in basal glucose transport in most tissues, consists of ten exons and encodes a 492 amino acid protein. Population studies have shown a strong association between the X1 allele of an XbaI restriction fragment length polymorphism of the GLUT1 gene and NIDDM. We therefore performed SSCP analysis in NIDDM subjects known to carry at least one X1 allele. Variant SSCP patterns were detected in exons 2, 4, 5 and 9. Sequence analysis of the SSCP variants revealed the presence, in all exons examined, of silent mutations consisting of single-nucleotide substitutions with no amino acid changes. Both NIDDM and obese patients showed a high frequency of polymorphism in the sequence (50% and 35%, respectively). We conclude that the GLUT1 gene is unlikely to play a role in the aetiology of NIDDM and obesity. However, the strong association between the GLUT1 gene and NIDDM, together with the recent family studies showing linkage between chromosome 1p and NIDDM warrant further studies on this chromosomal region.

Insulin resistance characterizes glucose uptake in skeletal muscle but not in the heart in NIDDM.

Skeletal muscle insulin resistance and coronary heart disease (CHD) often precede non-insulin-dependent diabetes mellitus (NIDDM). A recent study showed the myocardium of patients with CHD to be insulin resistant, independent of blood flow. We determined whether myocardial insulin resistance is a feature of NIDDM patients with no CHD. Skeletal muscle and myocardial glucose uptake were determined in 10 patients with NIDDM and 9 age- and weight-matched normal men of similar age and body mass index men using [18F]-2-fluoro-2-deoxy-D-glucose and positron emission tomography under normoglycaemic hyperinsulinaemic conditions. Whole body glucose uptake, as determined by the euglycaemic clamp technique, was significantly lower in the patients with NIDDM (35+/-3 micromol/kg body weight min) than the normal subjects (45+/-3 micromol/kg body weight x min, p < 0.02). Insulin-stimulated femoral muscle glucose uptake was significantly lower in the patients with NIDDM (71+/-6 micromol/kg muscle x min) than in the normal subjects (96+/-5 micromol/kg muscle x min, p < 0.01). Whole body glucose uptake was correlated with femoral muscle glucose uptake in the entire group (r=0.76, p < 0.001), in patients with NIDDM and in normal subjects. Rates of insulin-stimulated myocardial glucose uptake were comparable between the patients with NIDDM (814+/-76 micromol/kg muscle min) and the normal subjects (731+/-63 micromol/kg muscle min, p > 0.4). Whole body or femoral muscle, and myocardial glucose uptake were not correlated in all subjects, patients with NIDDM or normal subjects. We conclude that insulin resistance of the myocardium is not a feature of uncomplicated NIDDM.

The significance of the Trp 64 Arg mutation of the beta3-adrenergic receptor gene in impaired glucose tolerance, non-insulin-dependent diabetes mellitus, and insulin resistance in Japanese subjects.

It has been reported that the Trp 64 Arg mutation of the human beta3-adrenergic receptor (beta3-AR) gene is related to an earlier age of onset of non-insulin-dependent diabetes mellitus (NIDDM) and features of insulin resistance and weight gain in morbidly obese patients. However, such findings have not been consistent in varying ethnic populations. In the present study, we investigated the frequency of the Trp 64 Arg mutation of the human beta3-AR gene in Japanese control subjects (n = 253) and in NIDDM (n = 314) and impaired glucose tolerance (IGT) patients (n = 100). We compared the frequency of the mutation with the body-mass index (BMI) in these groups and with the metabolic clearance rate (MCR) of glucose in the NIDDM patients. A Trp 64 Arg mutation was observed in 36.7%, 31.6%, and 37.0% of the control, NIDDM, and IGT subjects, respectively. The frequency of the homozygotes for the mutation was 4.3%, 4.8%, and 3.0%, respectively. Neither the genotype frequency (Trp/Arg, Arg/Arg) nor the frequency of the mutated allele was significantly different among the three groups. The BMI of the subjects with the mutation was not significantly higher than that of the subjects without the mutation in each group. Furthermore, the allele frequency (A) was not different among the subjects with different BMIs (BMI < 22.0, 22.0 < or = BMI < or = 26.4, BMI > 26.4) in each group. In a separate group of NIDDM patients, the MCR of the subjects with intermediate BMIs (22.0 < or = BMI < or = 26.4) with the mutation tended to be lower than that of those without the mutation. In addition, the MCR of the subjects with the mutation in this group was significantly lower compared with that of those with a BMI less than 22. These results indicate that the Trp 64 Arg mutation of the beta3-AR gene may not contribute to the development of NIDDM or be a determinant of obesity in the Japanese population. However, the mutation may contribute to insulin resistance in NIDDM patients with an intermediate BMI.

Minimal influence of blood flow on interstitial glucose and lactate-normal and insulin-resistant muscle.

To study the regulation of the interstitial glucose concentration in skeletal muscle, nine control subjects and nine older and overweight non-insulin-dependent diabetes mellitus (NIDDM) subjects with extreme insulin resistance were investigated with microdialysis in the medial femoral muscle before and during a euglycemic insulin clamp. After an overnight fast, arterial plasma glucose concentration was 4.9 +/- 0.1 and 8.5 +/- 0.6 mmol/l (P < 0.001), respectively. The arterial-interstitial concentration ([a-i]) differences of glucose and lactate were 0.43 +/- 0.16 (P < 0.05) and -0.13 +/- 0.05 mmol/l, respectively, in normal subjects. In NIDDM subjects, [a-i] differences for glucose and lactate were nonsignificant. Muscle blood flow was similar in controls and NIDDM subjects. During the glucose clamp, the glucose [a-i] differences increased and the lactate [a-i] differences decreased significantly in both groups. The glucose 170 infusion rate was 8.0 +/- 0.77 vs. 3.2 +/- 0.51 mg.kg-1.min-1 (P < 0.001), and blood flow was 9.9 +/- 1.6 vs. 6.7 +/- 0.9 ml.100 g-1.min-1 (P < 0.05) in controls and NIDDM subjects, respectively. These results show that 1) the capillary wall is rate limiting for muscle glucose uptake and lactate release in control subjects but not in postabsorptive hyperglycemic insulin-resistant subjects, 2) vasodilation during insulin infusion does not prevent the increase in [a-i] difference of glucose in normal subjects, and 3) in severely insulin-resistant muscle, the [a-i] difference of glucose is not extended despite lack of vasodilation.

Effects of a protein meal on plasma amino acids, glucose and insulin in control and non insulin dependent diabetes mellitus

This study is concerned with the influence of a protein meal (250g beef steak) on plasma glucose, insulin and amino acids measured before and for 3 hours after feeding in control (C) and non insulin dependent diabetes mellitus (NIDDM) subjects. Plasma glucose which was 4.2±0.3 for C and 8.0±0.4 mM/l for NIDDM subjects during the fasting state, remained unchanged for the duration of the postprandial period. At that time plasma insulin levels were at 35.6±10.5 for C and at 98.2±13.6 μmol/l for NIDDM subjects. A rapid insulin release identified as the early cephalic phase of feeding was observed in both groups even if it was slightly delayed in NIDDM subjects. Two hours after feeding plasma insulin was increased by approximately 100% in both groups. At 180 min the plasma levels remained elevated in the NIDDM subjects but significantly declined in the controls. This increase in insulin in the presence of unchanged glycemia suggests an increase glucose utilization supported by an enhanced gluconeogenesis. Plasma levels of all branched-chain amino acids as well as of alanine and arginine, were significantly higher during the fasting state and increased more after the protein meal in NIDDM than in control subjects. The results for both groups of subjects show on the whole a high correlation between the plasma levels of insulin on one hand and those of arginine and alanine. The nature of this relationship is not different between the two groups; for instance the high values for plasma insulin observed in the NIDDM group correspond to high values for plasma arginine, alanine and total amino acids. Taken together these results suggest that in both groups, the unchanged glycemia following the protein meal, in spite of increased glucose utilization as evidenced by increased insulin secretion, is caused by enhanced gluconeogenesis possibly regulated primarily by alanine and arginine with the participation of branched-chain amino acids.

Blood pressure and coronary heart disease in NIDDM subjects at diagnosis: prevalence and risks in a Bangladeshi population

Overall obesity and central fat distribution are frequently accompanied by hyperglycemia, hypertension (HTN) and coronary heart disease (CHD) observed in developed nations and in South Asian migrants. This study attempts to estimate the prevalence of CHD and HTN and to assess the related risks among the newly diagnosed diabetics in the developing communities. From a total of 3583 non-insulin-dependent diabetes mellitus (NIDDM) and impaired glucose tolerance (IGT) subjects, the authors investigated 693 (M=295, F=398) randomly selected non-smokers of age 30–60 years. WHO diagnostic criteria were used for NIDDM and IGT. Systolic and diastolic hypertension (sHTN and dHTN) were defined as systolic blood pressure (SBP)≥140 and diastolic (DBP)≥90 mmHg. Diagnosis of CHD was based on electrocardiogram either on rest or on stress or both when equivocal. The overall prevalence of CHD in the NIDDM subjects was 18.6%. The prevalence rates of sHTN and dHTN were 23.2 and 13.6%, respectively. CHD and HTN did not differ significantly between male and female and between urban and rural subjects. CHD prevalence was significantly higher in the higher tertiles of age, SBP and DBP ( P<0.001, for all cases). Logistic regression showed that only the increasing age, high waist-to-hip ratio (WHR) and high BP were the independent risks for CHD. For sHTN, the independent risks were increased age and high body mass index (BMI) (kg/m 2). Regardless of sex and area, increased prevalence of CHD and HTN were found in the newly diagnosed diabetic subjects. Increased age, central obesity and HTN were the independent risks for CHD while advancing age and overall obesity was related to sHTN.

Disproportionately elevated proinsulin levels reflect the degree of impaired B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus.

An increased proportion of fasting proinsulin (PI) relative to immunoreactive insulin (IRI; increased PI/IRI) occurs in noninsulin-dependent diabetes mellitus (NIDDM). To determine whether the magnitude of the increase in PI/IRI is an indicator of the degree of reduced B cell secretory capacity, we measured fasting plasma glucose, PI, IRI, and PI/IRI and related them to maximal B cell secretory capacity (AIRmax) in 9 subjects with NIDDM [age, 61 +/- 3 yr; body mass index (BMI), 27.5 +/- 1.3 kg/m2; duration of NIDDM, 10.8 +/- 1.8 yr; mean +/- SEM] and in 10 healthy subjects matched for age and BMI (age, 61 +/- 6 yr; BMI, 27.9 +/- 1.5 kg/m2). AIRmax was quantified as the incremental insulin response to i.v. arginine at maximal glycemic potentiation (plasma glucose > 25 mmol/L). Mean fasting plasma glucose was 13.7 +/- 1.4 mmol/L (range, 7.5-18.3 mmol/L) in NIDDM subjects and 5.0 +/- 0.1 mmol/L in the controls. Fasting PI was higher in NIDDM (33.1 +/- 5.2) than in controls (9.4 +/- 2.5 pmol/L; P < 0.01), but IRI levels were similar (93.4 +/- 10.9 vs. 82.8 +/- 23.4 pmol/L; P = NS). The PI/IRI ratio was significantly elevated in NIDDM compared to control subjects (35.9 +/- 4.1% vs. 12.8 +/- 0.8%; P < 0.01). After elevation of the glucose level to 30.3 +/- 0.4 mmol/L (NIDDM) and 30.3 +/- 0.5 mmol/L (controls), AIRmax was quantified as 622 +/- 71 pmol/L in NIDDM and 1997 +/- 315 pmol/L in controls, (P < 0.001). The PI/IRI ratio correlated inversely with AIRmax in the NIDDM patients (r = -0.76; P < 0.01). We conclude that the magnitude of the elevation in fasting PI/IRI is related to the reduction in AIRmax. Thus, the fasting PI/IRI ratio appears to be a marker of the degree of reduced AIRmax in NIDDM.

Intrarenal arteriosclerosis and impairment of kidney function in NIDDM subjects.

It is currently under debate whether the pathogenesis of end-stage renal failure in non-insulin-dependent diabetes mellitus (NIDDM) is a consequence of microangiopathy alone. The aim of this study was to investigate intrarenal arteriosclerosis and its correlation with kidney function in NIDDM. In 36 diabetic subjects, and in 10 age- and sex-matched healthy control subjects we measured kidney volume and resistive index of the interlobar arteries by duplex Doppler ultrasonography. Clinical and metabolic parameters, renal function and vascular sequelae of the disease were also evaluated. In diabetic subjects resistive index (median 0.72, range 0.54-0.79) was higher than in control subjects (median 0.62, range 0.57-0.66) (2p < 0.002). Kidney volume and resistive index correlated with age (p < 0.004), body mass index (p < 0.001), mean blood pressure (p < 0.001), total and LDL cholesterol (p < 0.01) and creatinine clearance (p < 0.001 and < 0.01, respectively). Kidney volume also correlated with HbA1 (p < 0.01) and resistive index with uric acid (p < 0.01). Lower body macroangiopathy was associated with increased resistive index and reduced kidney volume (2p < 0.05), while upper body macroangiopathy and microangiopathy were not. Our data suggest that macroangiopathy rather than microangiopathy is mainly responsible for impairment of kidney function in NIDDM. The resistive index of interlobar arteries seems to be a reliable marker of intrarenal arteriosclerosis and can be used as a non-invasive, easily available parameter of its evolution.

Correlation between serum lipoprotein(a) and angiographic coronary artery disease in non-insulin-dependent diabetes mellitus.

To examine the impact of diabetic state on the concentrations of lipoprotein(a) [Lp(a)] in patients with non-insulin-dependent diabetes mellitus (NIDDM) and the correlation between angiographic coronary artery disease (CAD) and serum Lp(a) concentrations in NIDDM. In this cross-sectional study of 26 patients with NIDDM and 19 nondiabetic sex- and age-matched patients who underwent coronary angiography. CAD was assessed visually using coronary artery score (CAS), and plasma Lp(a) was measured by an enzyme-linked immunosorbent assay. The study was performed in an internal medicine clinic at a university hospital. Twenty-six age- and sex-matched patients with NIDDM and 19 control patients without diabetes. There was no significant difference between the Lp(a) concentrations of patients with NIDDM and nondiabetic subjects (P > 0.05). When patients with NIDDM were stratified by absence or presence of CAD, patients with CAD had higher levels of Lp(a) (P < 0.05). However, there was no significant correlation between the concentrations of Lp(a) and CAS (P > 0.05). Diabetic state does not have any impact on Lp(a) concentrations. Lp(a) excess seems to be atherogenic in patients with NIDDM as shown in nondiabetic patients in previous studies. Although diabetic patients with CAD have higher Lp(a) concentrations than the diabetic patients without CAD, Lp(a) levels were not correlated with CAS.

Plasma PAF acetylhydrolase in non-insulin dependent diabetes mellitus and obesity: effect of hyperinsulinemia and lovastatin treatment

Insulin resistance is characterized principally by impaired insulin-mediated glucose uptake which provokes a compensatory increase in pancreatic β-cell secretory activity. For a time this may produce well-controlled plasma glucose levels but as the insulin resistance worsens the augmented insulin production becomes inadequate to keep plasma glucose at euglycemia leading to the development of non-insulin dependent diabetes mellitus (NIDDM), accompanied by hyperinsulinemia and hyperglycemia. A number of metabolic defects are associated with NIDDM including obesity, hypercoagulability, cardiovascular disease risk factors such as hypertension and dyslipidemia and these constitute the insulin resistance syndrome. The identity of the biochemical factor that might link all these defects is not yet known. We have hypothsisized that platelet-activating factor (1- O-alkyl-2-acetyl- sn-glycero-3-phosphocholine, PAF) may be such a link. In this study, we measured plasma acetylhydrolase (EC.1.1.48), which degrades PAF to the inactive metabolise lyso-PAF, as a surrogate for PAF activity in three groups of hypercholesterolemic subjects: lean controls ( n=9), non-diabetic obese ( n=6) and NIDDM subjects ( n=6). The ages and body mass indices of the subjects were 46±3.1 and 24.2±2.2 for the lean controls, 52±2.5 and 28.7±0.9 for the NIDDM subjects and 60±2 and 27.6±2.1 for the obese, non-diabetic subjects (mean±S.E.M.). The measurements were made before and after therapy with the cholesterol-lowering drug lovastatin, a 3-hydroxy 3 methylglutaryl (HMG) coenzyme A reductase inhibitor (40 mg/day) for 3 months. Fasting plasma glucose (FPG) levels were 91±11, 96±3 and 146±11 mg/dl, for the lean, obese and NIDDM subjects, respectively, before therapy began. Lovastatin did not affect FPG in any of the three subject groups. Before treatment, the fasting plasma insulin (FPI) levels were 6.1±0.92, 10.83±2.03 and 14.68±3.64 mU/l for the lean, non-diabetic obese and NIDDM subjects, respectively. After lovastatin therapy only the obese group exhibited a significant change in FPI (15.35±2.47 mU/l) ( P<0.05). Total cholesterol levels were similar in all three groups both before and after lovastatin therapy but within each group lovastatin therapy significantly reduced the total cholesterol by 32, 29 and 34% in the lean, obese and NIDDM subject groups respectively ( P<0.0001). Lovastatin therapy reduced LDL-cholesterol levels by 40, 32and 46% in the lean, obese and NIDDM subjects, respectively, but produced no significant effect on HDL or triglyceride levels. Before therapy, the plasma acetylyhydrolase activities were 104±7, 164±7 and 179±7 nmol/ml per min in the lean, obese and NIDDM subjects, respectively. Lovastatin therapy reduced plasma acetylhydrolase levels to 70±7, 87±6 and 86±7 nmol/ml per min in the lean, obese and NIDDM subjects, respectively. Plasma acetylhydrolase activity was predominantly (>80%) associated with LDL cholesterol both before and after lovastatin treatment. Also, plasma acetylhydrolase activity significantly correlated with fasting plasma insulin levels before lovastatin therapy but not after. Taken together, this study clearly implicates PAF metabolism in three defects associated with the insulin resistance syndrome; hypercholesterolemia, obesity and NIDDM. Additionally, we conclude that chronic hyperinsulinemia may play a significant role in the production of plasma acetylhydrolase.

New variants in the glycogen synthase gene (Gln71His, Met416Val) in patients with NIDDM from eastern Finland.

Impaired glycogen synthesis after insulin stimulation accounts for most of the insulin resistance in patients with non-insulin-dependent diabetes mellitus (NIDDM). The glycogen synthase gene (GYS1), which encodes the rate-limiting enzyme for glycogen synthesis, is a promising candidate gene for NIDDM. Therefore, we screened all 16 exons of this gene by single-strand conformation polymorphism analysis in 40 patients with NIDDM (age 67 +/- 2 years, body mass index 28.2 +/- 0.6 kg/m2) from Taipalsaari, eastern Finland. The Gly464Ser variant (exon 11) and a silent polymorphism TTC342TTT (exon 7) have been reported previously. In addition, we found a new variant Gln71His (exon 2) and a new amino acid polymorphism Met416Val (exon 10). An additional sample of 65 patients with NIDDM and 82 normoglycaemic men (age 54 +/- 1 years, body mass index 26.3 +/- 1.4 kg/m2) were screened. The allele frequency of the TTC342TTT silent substitution was 0.29 in both NIDDM and normoglycaemic subjects. The Gln71His and Gly464Ser variants were found in 1 (1%) and 3 (3%) subjects, respectively, of the 105 NIDDM patients and in none of the 82 normoglycaemic men. The Met416Val polymorphism was found in 16 (15%) of the 105 NIDDM patients and in 14 (17%) of the 82 control subjects (all heterozygous). The Met416Val polymorphism was not associated with insulin resistance in two groups of normoglycaemic subjects. In conclusion, the new Gln71His and Met416Val substitutions and other variants of the glycogen synthase gene are unlikely to make a major contribution to insulin resistance and NIDDM in diabetic patients from eastern Finland.

Good metabolic and safety profile of troglitazone alone and following alcohol in NIDDM subjects

Drinking alcohol is associated with a recognised risk of hypoglycaemia. This double-blind, placebo-controlled study was designed to determine whether alcohol taken with the evening meal alters the gluco-regulatory response to troglitazone, (TR), an insulin action enhancer, in non-insulin-dependent diabetes mellitus (NIDDM) subjects to increase the risk of hypoglycaemia. In vitro studies conducted prior to the clinical study presented here showed no evidence of a pharmacokinetic interaction between the two drugs. A total of 23, diet-treated, NIDDM subjects received either TR, 200 mg once daily ( n=11) or placebo (PL) ( n=12) for 45 days. On days 42 and 45 subjects were given, on separate days, an alcohol challenge (AC), 0.6 mg/kg ethanol in orange juice and a control challenge, CC, orange juice alone, with the evening meal. Serum glucose, insulin, proinsulin-like molecules, C-peptide and lipids were measured during the study, for the 4 h after each challenge and the following morning (fasting). The over-night urine cortisol/creatinine ratio (an index of hypoglycaemia) was also determined. For the TR treated group, fasting serum glucose the next morning (adjusted geometric mean: 6.8 mmol/l for CC; 6.7 mmol/l for AC) and weighted mean were not statistically significantly different following AC compared to CC. Mean trough glucose for TR after the evening meal was 5.7 mmol/l following both the AC and CC. Analysis of the other parameters showed no symptomatic or pharmacodynamic evidence of an acute interaction between TR and alcohol. It can be concluded that occasional drinking of alcohol, with a meal, by TR-treated NIDDM patients is unlikely to be associated with an increased risk of hypoglycaemia.

Microalbuminuria and carotid artery intima-media thickness in nondiabetic and NIDDM subjects. The Insulin Resistance Atherosclerosis Study (IRAS).

Microalbuminuria is associated with cardiovascular mortality in subjects with non-insulin-dependent diabetes mellitus (NIDDM). However, little is known about this association in nondiabetic subjects. Specifically, it is not known whether microalbuminuria is related to an early stage of atherosclerosis manifested as increased intima-media thickness (IMT) of carotid arteries. We investigated the relationship between microalbuminuria and carotid artery IMT in 991 nondiabetic and 450 NIDDM subjects aged 40 to 69 years. Microalbuminuria was defined as albumin-to-creatinine ratio > or = 2 mg/mmol in a morning spot urine sample. B-mode ultrasound was used to assess the IMT of the common and internal carotid arteries. Altogether 13.9% of nondiabetic and 27.6% of NIDDM subjects had microalbuminuria, and 31.1% of nondiabetic and 50.8% of NIDDM subjects had hypertension. Subjects with microalbuminuria had greater common carotid artery (CCA) IMT than those without microalbuminuria (nondiabetic: 0.84 +/- 0.02 versus 0.80 +/- 0.01 mm, P = .010; NIDDM: 0.89 +/- 0.02 versus 0.86 +/- 0.01 mm, P = .152; combined: 0.86 +/- 0.01 versus 0.82 +/- 0.01, P = .005). The association of microalbuminuria and CCA IMT was independent of age, sex, ethnicity, smoking, and lipoprotein levels. Although further adjustment for hypertension in the multivariate linear regression analysis attenuated the difference in CCA IMT between subjects with and without microalbuminuria, this difference continued to be significant (combined: 0.86 +/- 0.01 versus 0.83 +/- 0.01, P = .015). In contrast to CCA IMT, microalbuminuria was not related to ICA IMT. Microalbuminuria was associated with increased CCA IMT. This relationship was only partly mediated by hypertension. Thus, microalbuminuria is related to atherosclerosis at an early stage of the disease process.

A long-term comparison between enalapril and captopril on insulin sensitivity in normotensive non-insulin dependent diabetic volunteers

There are conflicting reports about the effects of angiotensin converting enzyme inhibitors on insulin sensitivity and glycaemic control. In addition, the chronic effects of ACEI on insulin sensitivity in normotensive but insulin resistant individuals have been controversial. To determine the long-term effects of low-dose captopril or enalapril on insulin sensitivity and lipid parameters in normotensive non-insulin dependent diabetic volunteers. Twenty-eight normotensive non-insulin dependent diabetes mellitus subjects on diet alone or diet plus oral hypoglycaemic agents were randomized in a single-blind cross-over study to receive either captopril (12.5 mg daily) or enalapril (5 mg daily). Initially, captopril was compared with enalapril for 28 days with a 28-day washout period between drug regimens. For the long-term study, the subjects then remained on the second ACEI for a further 11 months. Insulin sensitivity was measured using the isoglycaemic hyperinsulinaemic clamp (insulin infusion rate 20 mIU/kg/min) at the start and completion of each part of the cross-over study and then at 3, 6 and 12 months of drug therapy. Fasting glucose, insulin, HbA1, lipids and lipoproteins were measured at the start of each clamp. No first or second order carry-over effects were demonstrated between the ACEIs. No differences were detected between enalapril and captopril on insulin sensitivity at any of the time points. Statistically significant hypotension was avoided, and at doses used the ACEIs did not modify any parameters of glycaemic control over the 12-month study period. There were no significant alterations in plasma cholesterol, triglycerides, HDL cholesterol or Apo A1 levels during the study. Long-term low-dose ACEIs (captopril/enalapril) do not modify insulin sensitivity, glycaemic control or lipids in normotensive non-insulin dependent diabetic subjects.

Increased soluble fibrin monomer and soluble thrombomodulin levels in non-insulin-dependent diabetes mellitus.

We measured the plasma levels of fibrinogen, D-dimer, thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC), soluble fibrin monomer (SFM), tissue-type plasminogen activator (t-PA) and thrombomodulin (TM) in patients with non-insulin-dependent diabetes mellitus (NIDDM). There were no significant differences in the hemostatic parameters between the 77 patients with NIDDM and healthy control subjects, although the plasma levels of fibrinogen, D-dimer, TAT, and PPIC in the NIDDM patients were slightly higher than those in the healthy controls. Among the NIDDM patients divided into three groups by the urinary albumin excretion (UAE) level, there was no significant difference in age or sex among the normo-, micro-, and macroalbuminuria groups, and the HbA1C level in the micro- and macroalbuminuria groups were slightly higher than those in the normoalbuminuria group. There was no significant difference in activated partial thromboplastin time, prothrombin time, fibrinogen, TAT, PPIC, D-dimer, or t-PA among these three groups. The plasma SFM and TM levels in the macroalbuminuria group were significantly higher than those in the normo- and microalbuminuria groups. The relationships between HbA1C and the hemostatic parameters were poor, but the plasma TM and SFM levels were significantly correlated with the urine albumin index.