NIDDM Subjects Research Articles

Comparison of Obese NIDDM and Nondiabetic Women: Short‐ and Long‐Term Weight Loss

Previous research suggests that overweight patients with diabetes lose less weight than nondiabetics. We compared the response of obese women with NIDDM to nondiabetic controls, matched for age and weight, to a behavior weight loss program. Forty-three overweight women (20 NIDDM, 23 nondiabetic) participated in the study. NIDDM and nondiabetic subjects were treated together and received the same 16-week behavioral weight loss program. Dependent measures included weight, 3-day food records, physical activity, fasting plasma glucose, and questionnaires assessing eating behavior and depressive symptomatology. Weight loss of NIDDM and nondiabetic subjects at posttreatment was comparable (-7.4 +/- 5.3 kg vs. -6.4 +/- 3.8 kg, respectively). Changes in caloric intake, eating behavior, exercise and depressive symptomatology were also similar between the two groups. However, during the 1-year follow-up period, NIDDM subjects regained 5.4 +/- 6.1 kg compared to 1.0 +/- 6.7 kg for nondiabetics (p = .058). These data indicate that NIDDM subjects can lose as much weight as their nondiabetic peers during active treatment. Once treatment terminated, however, NIDDM subjects demonstrated poor weight loss maintenance. Thus the added motivation that comes from having diabetes and seeing improvements in glycemic control with weight loss were not sufficient to improve long term weight loss in diabetic subjects. A continuous care model of weight control may be particularly necessary for overweight patients with type II diabetes.

Relationship between habitual diet and blood glucose and lipids in non-insulin dependent diabetes (NIDDM)

The relationships (adjusted for age, sex, diabetes duration and BMI) between habitual diet and blood glucose and lipids in NIDDM subjects from 7 cities in Canada were studied using duplicate 3-day diet records and measurements of fasting plasma glucose (FPG), glycosylated haemoglobin (HbAlc), serum total (TC) and HDL cholesterol and triglycerides (TG). In subjects treated by diet alone (n=75), HbAlc was inversely related to carbohydrate intake (r= −0.302, p=0.01) and directly to diet glycaemic index (r=0.321, p<0.01). In subjects on metformin (n=82), FPG was inversely related to dietary fibre (r=−0.265, p<0.02). In insulin-treated subjects (n=87), HbAlc was inversely related to carbohydrate (r=−0.303, p<0.01), fibre (r=−0.345, P<0.01) and simple sugars (r= −0.219, p<0.05) and positively to fat (r=0.313, p<0.01). Carbohydrate intake tended to be inversely related to HDL (p<0.05 only in subjects on insulin) but was not related to TG. Diet glycaemic index was related to TG in insulin-treated subjects with raised TG (r=0.504, p<0.02). These results suggest that high carbohydrate and fibre intakes and low diet glycaemic index may be associated with improved blood glucose control in some persons with NIDDM, especially those treated with diet alone or insulin. There was no evidence that high intake of carbohydrate or simple sugars was related to raised serum triglycerides.

Compositional HDL changes induced by n3FAs supplementation in microalbuminuric NIDDM subjects

Compositional HDL changes induced by n3FAs supplementation in microalbuminuric NIDDM subjects

Prolongation of near-normoglycemic remission in black NIDDM subjects with chronic low-dose sulfonylurea treatment

Prolongation of near-normoglycemic remission in black NIDDM subjects with chronic low-dose sulfonylurea treatment

Intranasal Insulin: the Effects of Three Dose Regimens on Postprandial Glycaemic Profiles in Type II Diabetic Subjects

In both fasting normal and diabetic subjects, nasally administered insulin achieves significant falls in plasma glucose concentrations. Repeated administration before and during a meal has been necessary to lower postprandial glycaemic excursion in subjects with NIDDM. We have studied the use of Novolin Nasal which employs a non-irritant, lecithin-based enhancer as a vehicle for human insulin, on postprandial glucose profiles in NIDDM subjects to determine efficacy, optimal dose frequency, and tolerability. Seventeen NIDDM subjects (15 men, 2 women) participated in a randomized, partially blinded, placebo-controlled, crossover trial of three active treatment regimens (nasal insulin, 120 U at 0 min, 60 U at 0 and +20 min or 120 U at +20 min) in relation to a standardized mixed meal given at 0 min. All active treatments significantly reduced postprandial glucose concentrations compared to placebo. Intranasal insulin given at 0 min at a dose of 60 U or 120 U resulted in a 50% reduction in postprandial incremental glucose compared to placebo over the first 2 h, whereas treatment with 60 U both at 0 and 20 min lead to a 70% reduction over the 240 min postprandial period. Post-prandial intravenous insulin was the least effective. There were no episodes of symptomatic hypoglycaemia. Local tolerability was excellent with only four reports of transient nasal irritation out of a total of 68 doses. The delivery device was accurate with intra-device CV of delivered dose of 4.8%.(ABSTRACT TRUNCATED AT 250 WORDS)

Peptide-based radioimmunoassay for the two isoforms of the human insulin receptor

The insulin receptor exists in two isoforms differing by the absence (HIR-A) or presence (HIR-B) of 12 amino acids in the COOH-terminus of the α-subunit as a consequence of alternative splicing of exon 11. In this study, we developed a radioimmunoassay for the two isoforms employing antibodies raised against two peptides, one (Pep-12) corresponding to residues encoded by exon 11, and the other (Pep-13) corresponding to a COOH-terminal domain of the α-subunit which is common to both HIR-A and HIR-B isoforms. These peptides were iodinated and used as both ligands and standards. The assay is specific, highly reproducible, and sensitive with a detection limit of 10 fmol of receptor. One mole of purified insulin receptor, measured by Scatchard analysis, is read as one mole of receptor in the radioimmunoassay with either Pep-12 or Pep-13 as standards. The radioimmunoassay is applicable to the measurement of total content and relative abundance of the two isoforms in extracts from various tissues. We applied the radioimmunoassay to measure the relative abundance of the two isoforms in fat and muscle from normal, obese non-diabetic and non-insulin-dependent diabetic (NIDDM) subjects. Results demonstrate that expression of the low-affinity HIR-B form is significantly increased in obese and NIDDM subjects compared with control subjects. In addition, the increased expression of the HIR-B isoform was significantly correlated with both body mass index (r=0.52; p=0.006) and fasting glucose levels (r=0.59; p=0.001).

Multiple defects of both hepatic and peripheral intracellular glucose processing contribute to the hyperglycaemia of NIDDM

Non-insulin-dependent diabetic (NIDDM) patients were studied during a modified euglycaemic state when fasting hyperglycaemia was normalized by a prior (−210 to −150 min) — and later withdrawn (−150–0 min) — intravenous insulin infusion. Glucose metabolism was assessed in NIDDM patients (n=10) and matched control subjects (n=10) using tritiated glucose turnover rates, indirect calorimetry and skeletal muscle glycogen synthase activity determinations. Total and non-oxidative exogenous glycolytic flux rates were measured using appearance rates of tritiated water. A+180 min euglycaemic hyperinsulinaemic (40 mU·m−2·min−1) clamp was performed to determine the insulin responsiveness of the various metabolic pathways. Plasma glucose concentration increased spontaneously during baseline measurements in the NIDDM patients (−120 to 0 min: 4.8±0.3 to 7.0±0.3 mmol/l; p<0.01), and was primarily due to an elevated rate of hepatic glucose production (3.16±0.13 vs 2.51±0.16 mg·kg FFM−1·min−1; p<0.01). In the NIDDM subjects baseline glucose oxidation was decreased (0.92±0.17 vs 1.33±0.14 mg·kg FFM−1·min−1; p<0.01) in the presence of a normal rate of total exogenous glycolytic flux and skeletal muscle glycogen synthase activity. The simultaneous finding of an increased lipid oxidation rate (1.95±0.13 vs 1.61±0.07 mg·kg FFM−1·min−1; p=0.05) and increased plasma lactate concentrations (0.86±0.05 vs 0.66±0.03 mmol/l; p=0.01) are consistent with a role for both the glucose-fatty acid cycle and the Cori cycle in the maintenance and development of fasting hyperglycaemia in NIDDM during decompensation. Insulin resistance was demonstrated during the hyperinsulinaemic clamp in the NIDDM patients with a decrease in the major peripheral pathways of intracellular glucose metabolism (oxidation, storage and muscle glycogen synthase activity), but not in the pathway of non-oxidative glycolytic flux which was not completely suppressed during insulin infusion in the NIDDM patients (0.55±0.15 mg·kg FFM−1·min−1; p<0.05 vs 0; control subjects: 0.17±0.29; NS vs 0). Thus, these data also indicate that the defect(s) of peripheral (skeletal muscle) glucose processing in NIDDM goes beyond the site of glucose transport across the cell membrane.

Sulfonylurea therapy improves glucose disposal without changing skeletal muscle GLUT4 levels in noninsulin-dependent diabetes mellitus subjects: a longitudinal study.

A major pathological feature of noninsulin-dependent diabetes (NIDDM) is defective insulin-stimulated glucose transport in skeletal muscle. When NIDDM subjects are assessed as a group, GLUT4 gene expression in skeletal muscle varies widely and is not different from that in controls. Thus, longitudinal studies are needed to assess whether changes in GLUT4 expression in muscle of NIDDM subjects could be responsible for changes in glucose disposal. The question is timely because recent studies in transgenic mice show that increasing GLUT4 expression can increase insulin-stimulated glucose uptake in vivo and in vitro. Here we use a longitudinal design to investigate the effects of 8 weeks of therapy with the sulfonylurea gliclazide on glycemic control, glucose tolerance, insulin-stimulated glucose disposal, and GLUT4 expression in muscle of 10 obese NIDDM subjects. Subjects were on a weight-maintaining diet. Gliclazide treatment results in increased serum C-peptide, decreased hemoglobin-A1c, decreased glucose excursion on glucose tolerance test, and 35% increased insulin-stimulated glucose disposal. Gliclazide therapy is not associated with any change in DNA or protein content per g muscle or any alteration in GLUT4 levels expressed either per microgram membrane protein or per DNA. In summary, the improvement in glycemic control and glucose disposal in NIDDM subjects receiving gliclazide therapy cannot be explained by increased expression of GLUT4 in muscle. Thus, therapeutic effects on insulin-stimulated glucose disposal can be achieved in NIDDM subjects without altering GLUT4 expression in muscle.

In vivo and in vitro studies of vanadate in human and rodent diabetes mellitus.

In vivo vanadate and vanadyl have been shown to mimic the action of insulin and to be effective treatment for animal models of both Type I and Type II diabetes. The molecular mechanism of action of the vanadium salts on insulin sensitivity remains uncertain, and several potential sites proposed for the insulin-like effects are reviewed. In human trials, insulin sensitivity improved in patients with NIDDM, as well as in some patients with IDDM after two weeks of treatment with sodium metavanadate. This increase in insulin sensitivity was primarily due to an increase in non-oxidative glucose disposal, whereas oxidative glucose disposal and both basal and insulin stimulated suppression of hepatic glucose output (HGP) were unchanged. Clinically, oral vanadate was associated with a small decrease in insulin requirements in IDDM subjects. Of additional benefit, there was a decrease in total cholesterol levels in both IDDM and NIDDM subjects. Furthermore, there was an increase in the basal activities of MAP and S6 kinases to levels similar to the insulin-stimulated levels in controls, but there was little or no further stimulation with insulin was seen. Further understanding of the mechanism of vanadium action may ultimately be useful in the design of drugs that improve glucose tolerance.

Vanadate as an oral antidiabetic agent

Today's need for effective oral glucose lowering agents and the recent advances in the understanding of the molecular mechanisms of insulin action have increased attention to the use of vanadate as an oral euglycaemic agent. Vanadate has metabolic actions like insulin. It is efficacious in rodent models of insulin-dependent diabetes (IDDM) and non-insulin-dependent diabetes (NIDDM). Moreover, recent clinical trials of two to three week duration in human NIDDM and IDDM subjects demonstrated that oral vanadate improved insulin sensitivity in all NIDDM subjects and some IDDM subjects. No major side effects were observed. Although vanadate is a potent protein-tyrosine phosphatase (PTPase) inhibitor, the precise glucose lowering mechanism is debatable since the metal is unstable and it is metabolised by cells. Recently chemists have taken advantage of the complex chemical properties of vanadate and have synthesised a variety of vanadium derivatives that are much more potent than vanadate. Some show in vitro en...

Is intima-media thickening present in non-diabetic siblings of NIDDM subjects?

Is intima-media thickening present in non-diabetic siblings of NIDDM subjects?

Impact of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic nephropathy

Impact of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic nephropathy

Impact of Lisinopril and Atenolol on Kidney Function in Hypertensive NIDDM Subjects With Diabetic Nephropathy

Diabetic nephropathy is characterized by hypertension and a relentless decline in kidney function. Angiotensin-converting enzyme inhibitors have been claimed to preserve kidney function better than an equal blood pressure (BP) reduction with conventional antihypertensive treatment (renoprotection). We compared the effect on kidney function of lisinopril (10-20 mg/day) and atenolol (50-100 mg/day) in hypertensive NIDDM patients (mean age 60 +/- 8 years) with diabetic nephropathy. Forty-three (21 lisinopril and 22 atenolol) patients were enrolled in a 1-year randomized double-blind parallel study. Eight patients dropped out, and the results for the remaining 35 patients (16 lisinopril and 19 atenolol) are presented. Diuretics were required in 10 of 16 lisinopril patients and 12 of 19 atenolol patients. The following variables were measured: 24-hour ambulatory BP (Takeda TM2420), albuminuria (enzyme-linked immunosorbent assay), fractional albumin clearance, and glomerular filtration rate (GFR) ([51Cr]EDTA technique). The average reduction in mean arterial BP during the 12 months was identical in the two groups 12 +/- 2 vs. 11 +/- 1 mmHg in the lisinopril and atenolol group, respectively. Albuminuria was on average reduced 45% in the lisinopril group vs. 12% in the atenolol group (P < 0.01), and fractional albumin clearance was on average reduced 49% in the lisinopril group vs. 1% in the atenolol group (P < 0.05). GFR declined identically in the two groups 11.7 +/- 2.3 vs. 11.6 +/- 2.3 ml.min-1.year-1 in the lisinopril and atenolol groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

NIDDM and Its Metabolic Control Predict Coronary Heart Disease in Elderly Subjects

The aim of this study was to evaluate whether noninsulin-dependent diabetes (NIDDM) and its metabolic control and duration predict coronary heart disease (CHD) events during a 3.5-year follow-up in a randomly selected Finnish population sample 65-74 years of age at baseline. Of 1,298 subjects participating in the baseline study, 1,069 were nondiabetic and 229 had NIDDM. During the follow-up, 3.4% of nondiabetic and 14.8% of NIDDM subjects died from CHD or had a nonfatal myocardial infarction (MI). The impact of NIDDM on CHD mortality and morbidity was more marked in women than in men. Odds ratios (ORs) and their 95% confidence intervals for CHD death and nonfatal MI in women with NIDDM compared with women with normal glucose tolerance were 11.7 (3.8-36.4) and 4.7 (3.6-6.1). In men, the corresponding ORs were 0.43 (0.1-1.9) and 1.4 (0.6-3.2). In multiple logistic regression analyses including all study subjects, NIDDM (P < 0.01), male sex (P < 0.05), and previous MI (P < 0.01) predicted CHD death (n = 45). NIDDM (P < 0.01), male sex (P < 0.05), previous MI (P < 0.05), current smoking (P < 0.001), systolic blood pressure (P < 0.001), and low high-density lipoprotein cholesterol (P < 0.01) predicted all CHD events (CHD death or nonfatal MI) (n = 107). In NIDDM subjects, only glycated hemoglobin A1c (GHbA1c) at baseline (P < 0.01) and duration of diabetes (P < 0.05) predicted CHD death (n = 15) and all CHD events (n = 33). There was a significant increase in the risk of CHD death and all CHD events in NIDDM subjects with GHbA1c levels higher than 7.0% compared with diabetic subjects with lower GHbA1c (ORs 4.3 [1.1-16.7] and 2.2 [1.0-5.1]). In conclusion, NIDDM and its metabolic control and the duration of diabetes are important predictors of CHD in elderly subjects, particularly in women.

α‐Glucosidase inhibitors in diabetes: efficacy in NIDDM subjects

With alpha-glucosidase inhibitors generally improved metabolic control is achieved in NIDDM patients regardless of whether acarbose is administered in addition to other oral anti-diabetic agents or to diet alone. The most significant finding is the reduction of postprandial blood glucose concentrations. Long-term studies show a decrease in glycosylated haemoglobin and often also in fasting blood glucose levels. Placebo-controlled studies have proven that postprandial insulin concentrations are decreased under acarbose treatment while fasting plasma insulin is usually unchanged. The major side-effects of acarbose treatment involve the gastrointestinal system and include flatulence, abdominal discomfort and diarrhoea. Symptoms diminish with treatment time and are less severe when the treatment is started with low doses. Acarbose should usually be initiated as a 50 mg dose immediately before each major carbohydrate containing meal. Monotherapy with acarbose does not cause hypoglycaemia, however, hypoglycaemia may occur with combination of sulphonylurea or insulin treatment by the well-known reasons. In this case hypoglycaemia has to be treated by taking glucose.

Efficacy of α‐glucosidase inhibitors on lipids in NIDDM subjects with moderate hyperlipidaemia

This paper summarizes literature data concerning the action of acarbose, an alpha-glucosidase inhibitor, on the concentrations of plasma lipids. Clinical trials in which acarbose has been used in the treatment of non-insulin-dependent diabetics have sometimes shown that it reduces serum triglycerides while it has little or no effect on serum cholesterol levels. The results of a randomized double-blind placebo-controlled study lasting 24 weeks are discussed in more detail. Under the controlled conditions, the effects of acarbose treatment on fasting concentrations of cholesterol, HDL-cholesterol, and triglycerides did not reach statistical significance for the entire patient group. However, in the highest tertile of initial cholesterol concentrations acarbose treatment led to significant lowering of the cholesterol concentration and of the total-to-HDL-cholesterol ratio. The most important benefits of acarbose were observed after a test meal given on day 0 and on week 24 of treatment. The triglyceride increment 1 h postprandial was significantly lowered. This was associated by a significant decrease of the insulin increment. Reduction of hyperinsulinaemia appears to be the mechanism by which acarbose treatment can improve plasma lipid concentrations.

Glucose and Insulin Responses in Isolated Human Lymphocytes Reflect in Vivo Status: Effects of VLCD Treatment

Human lymphocyte growth response to mitogen was examined in vitro under different conditions to monitor aspects of carbohydrate utilization in three groups: obese nondiabetic, obese/NIDDM, and normal-weight individuals. Although lymphocyte growth capacity in minimal medium for these three groups was found to be similar at a glucose concentration of 72 μg/ml in the absence of insulin or glycerol, differences in mitogen-stimulated growth were observed at lower glucose concentrations or in the presence of insulin or glycerol. Interestingly, these metabolic alterations in lymphocytes can be normalized by treating obese and obese/NIDDM subjects with a very low calorie diet (VLCD) regimen. The results of this study indicate that lymphocyte culture in a defined medium may provide a mechanism to examine different metabolic states and to evaluate treatment regimens (diet, exercise, etc.) for obese and NIDDM subjects.

Insulin-Receptor Tyrosine Kinase Activity is Decreased in Erythrocytes from Non-Obese Patients with NIDDM

We have examined insulin binding, and insulin receptor associated tyrosine kinase activity in detergent solubilized and Ricin II-agarose purified receptor preparations from erythrocytes of obese and non-obese subjects with normal glucose tolerance and non-obese patients with NIDDM. Insulin receptor activity, as assessed by [125I Tyr A14] insulin binding, was significantly lower in erythrocyte preparations from the obese group when compared with similar preparations from non-obese subjects, with either normal glucose tolerance or NIDDM. The affinity of the receptor for insulin, however, was reduced in both obese subjects and patients with NIDDM as compared to non-obese subjects with normal glucose tolerance. Insulin receptor tyrosine kinase activity, measured in the absence (basal) and presence of insulin (0.3-3000 nM), was decreased in obese and NIDDM subjects with normal glucose tolerance and in patients with NIDDM. Insulin sensitivity, measured as the dose of insulin required for half-maximal activation of kinase activity, however, was comparable among three groups. In contrast, insulin-stimulated tyrosine kinase activity, when normalized to insulin binding activity, was unchanged in both non-obese and obese subjects with normal glucose tolerance, but was reduced approximately 60% in the NIDDM group. These findings indicate that the functional behavior of insulin receptor-kinase signaling system is markedly impaired in non-obese patients with NIDDM. Furthermore, the insulin receptor-tyrosine kinase defect (i.e. decrease in activity) observed in patients with NIDDM is probably related to a reduction in coupling efficiency between insulin binding and the activation of the receptor tyrosine kinase activity.

The interrelationship between impaired glucose tolerance and other risk factors for cardiovascular disease: Is it a predictor for cardiovascular disease?

Glucose intolerance and cardiovascular risk factors were assessed among 215 subjects aged 27-86 years in Ho-long, Taiwan. An oral glucose tolerance test (OGTT) was normal in 107 subjects, impaired in 41 subjects, and abnormal in 67 subjects (as noninsulin dependent diabetes mellitus, NIDDM). Body fatness, blood pressure, carbohydrate and lipid metabolic factors were examined. One-way ANCOVA was used to compare age- and/or BMI-adjusted differences among these groups. Male subjects with NIDDM and impaired glucose tolerance (IGT) had higher systolic (SBP) and diastolic (DBP) blood pressures, plasma insulin (fasting and 1-hour after OGTT), serum triglycerides (TG), heavier body weight, and larger BMI than normal. IGT subjects were also found to have higher TG, insulin (2-hour) and larger insulin area under curve (IAUC) after OGTT than NIDDM. In females, subjects with NIDDM had higher TG, insulin (fasting and 1-hour after OGTT), and larger IAUC than normal. Moreover, female IGT subjects were also found to have significantly higher SBP, DBP, insulin (1-and 2-hour after OGTT), and larger IAUC than both normal and NIDDM subjects. These results suggest that adverse cardiovascular risk factors are present not only in NIDDM subjects, but also in IGT subjects.

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