Obese Non-insulin-dependent Diabetes Mellitus Patients Research Articles

Vagal control of heart rate in obese non-insulin dependent diabetes mellitus patients

The aim of study was to analyse the vagal control of heart rate in non-insulin dependent diabetes mellitus (NIDDM) patients with different body mass. Age and gender matched NIDDM patients (men, 61±1.8 yr, Hb A1c 8.1±0.9%,) were divided in two groups according to the body mass index, with overweight (n=14; BMI>30 kg/m2) and without overweight (n=17; BMI<25 kg/m2). Beat-to-beat HR and finger mean arterial pressure were monitored noninvasively. The carotid baroreceptors were stimulated applying neck suction (-60 mm Hg, for 5s) 6 times at rest and with 15s intervals during handgrip for 60 s with force 50% of maximal voluntary contraction. HbA1c was significantly higher in obese patients (9.6±0.2 vs 7.7±0.6%; p<0.05). Finger mean arterial pressure was increased (109±2.9 vs 95±2.7 mm Hg; p<0.05), heart rate didn't differ significantly, but bradycardic reaction (1.2±0.6 vs 2.7±0.8 bpm; p<0.05) to baroreflex activation was reduced in NIDDM patients with overweight. The amplitude of pressor reaction (41±4 vs 30±2.6 mm Hg; p<0.05) was decreased in patients with overweight. Although heart rate (73±2.5 vs 78±3.3 bpm; NS) didn't differ significantly at rest in analysed groups, the amplitude of heart rate acceleration (23±2.7 vs 11 ±1.7 bpm; p<0.05) at 60th s of handgrip was decreased in obese patients and heart rate non-linear acceleration trajectory was altered, especially the rapid component of the curve during the first 10 s of exercise which is connected with reduction of cardiac vagal tone. The bradycardic reaction to baroreflex activation progressively decreased during whole static exercise in patients without overweight, but in obese patients it already disappeared in the first 15 s of handgrip. The present data show that vagal control of heart rate was altered in obese NIDDM patients, which probably is related with worse glycaemic control.

Serum levels of tumor necrosis factor-alpha are increased in obese patients with noninsulin-dependent diabetes mellitus.

To clarify the significance of the serum levels of tumor necrosis factor-alpha (TNF-alpha) in the mechanism of insulin resistance, we studied 12 obese patients with noninsulin-dependent diabetes mellitus (NIDDM). We evaluated the relationship of TNF-alpha levels with the visceral, subcutaneous, and total fat areas measured by computed tomography (CT), and with insulin resistance evaluated by the glucose infusion rate (GIR) observed during an euglycemic hyperinsulinemic clamp study. Controls consisted of 12 normal subjects and 12 nonobese patients with NIDDM. TNF-alpha levels were measured using a high sensitivity enzyme-linked immunosorbent assay. Following admission, all patients with NIDDM participated in a 4-week program of diet and exercise. After this treatment, we evaluated the relationship of the serum levels of TNF-alpha with the area of body fat, the GIR, and the resultant change in the TNF-alpha level. Serum levels of TNF-alpha in the obese patients with NIDDM significantly exceeded those observed in normal subjects (P < 0.01) or in the nonobese patients with NIDDM (P < 0.01). Serum levels of TNF-alpha in obese NIDDM patients showed a significant positive correlation with the area of visceral fat before (r = 0.662, P < 0.03) and after (r = 0.508, P < 0.05) the treatment; similar correlation was observed in all patients with NIDDM before (r = 0.537, P < 0.02) and after (r = 0.430, P < 0.05) the treatment. Serum levels of TNF-alpha in obese NIDDM patients showed a significant negative correlation with GIR after the treatment (r = -0.595, P < 0.05). Serum levels of TNF-alpha were significantly reduced in the obese patients with NIDDM after the treatment (P < 0.01), while those in the nonobese NIDDM patients were unchanged. These results suggest that serum TNF-alpha levels may play an important role in mechanism of insulin resistance associated with obesity.

Skeletal muscle peroxisome proliferator- activated receptor-gamma expression in obesity and non- insulin-dependent diabetes mellitus.

The two isoforms of peroxisome proliferator-activated receptor-gamma (PPARgamma1 and PPARgamma2), are ligand-activated transcription factors that are the intracellular targets of a new class of insulin sensitizing agents, the thiazolidinediones. The observation that thiazolidinediones enhance skeletal muscle insulin sensitivity in obesity and in patients with non-insulin-dependent diabetes mellitus (NIDDM), by activating PPARgamma, and possibly by inducing its expression, suggests that PPARgamma expression in skeletal muscle plays a key role in determining tissue sensitivity to insulin, and that PPARgamma expression may be decreased in insulin resistant subjects. We used a sensitive ribonuclease protection assay, that permits simultaneous measurement of the two isoforms, to examine the effects of obesity and NIDDM, and the effects of insulin, on skeletal muscle levels of PPARgamma1 and PPARgamma2 mRNA. We studied seven patients with NIDDM (body mass index, 32+/-1 kg/m2), seven lean (24+/-1 kg/m2), and six obese (36+/-1 kg/m2) normal subjects. Biopsies from the vastus lateralis muscle were taken before and after a 5-h hyperinsulinemic (80 mU/m2 per minute) euglycemic clamp. The obese controls and NIDDM patients were insulin resistant with glucose disposal rates during the last 30 min of the clamp that were 67 and 31%, respectively, of those found in the lean controls. PPARgamma1, but not PPARgamma2 mRNA was detected in skeletal muscle at 10-15% of the level found in adipose tissue. No difference was found in PPARgamma1 levels between the three groups, and there was no change in PPARgamma1 levels after 5 h of hyperinsulinemia. In obese subjects, PPARgamma1 correlated with clamp glucose disposal rates (r = 0.92, P < 0.01). In the lean and NIDDM patients, muscle PPARgamma1 levels correlated with percentage body fat (r = 0.76 and r = 0.82, respectively, both P < 0.05) but not with body mass index. (a) skeletal muscle PPARgamma1 expression does not differ between normal and diabetic subjects, and is not induced by short-term hyperinsulinemia; (b) skeletal muscle PPARgamma1 expression was higher in subjects whose percent body fat exceeded 25%, and this may be a compensatory phenomenon in an attempt to maintain normal insulin sensitivity.

Interaction between BTBR and C57BL/6J genomes produces an insulin resistance syndrome in (BTBR x C57BL/6J) F1 mice.

Insulin resistance is a common syndrome that often precedes the development of noninsulin-dependent diabetes mellitus (NIDDM). Both diet and genetic factors are associated with insulin resistance. BTBR and C57BL/6J (B6) mice have normal insulin responsiveness and normal fasting plasma insulin levels. However, a cross between these two strains yielded male offspring with severe insulin resistance. Surprisingly, on a basal diet (6.5% fat), the insulin resistance was not associated with fasting hyperinsulinemia. However, a 15% fat diet produced significant hyperinsulinemia in the male mice (twofold at 10 weeks; P < .05). At 10 weeks of age, visceral fat contributed approximately 4.3% of the total body weight in the males versus 1.8% in females. In the males, levels of plasma triacylglycerol and total cholesterol increased 40% and 30%, respectively, compared to females. Plasma free fatty acid concentrations were unchanged. Oral glucose tolerance tests revealed significant levels of hyperglycemia and hyperinsulinemia 15 to 90 minutes after oral glucose administration in the male mice. This was particularly dramatic in males on a 15% fat diet. Glucose transport was examined in skeletal muscles in (BTBR x B6)F1 mice. In the nonhyperinsulinemic animals (females), insulin stimulated 2-deoxyglucose transport 3.5-fold in the soleus and 2.8-fold in the extensor digitorum longus muscles. By contrast, glucose transport was not stimulated in the hyperinsulinemic male mice. Hypoxia stimulates glucose transport through an insulin-independent mechanism. This is known to involve the translocation of GLUT4 from an intracellular pool to the plasma membrane. In the insulin-resistant male mice, hypoxia induced glucose transport as effectively as it did in the insulin-responsive mice. Thus, defective glucose transport in the (BTBR x B6)F1 mice is specific for insulin-stimulated glucose transport. This is similar to what has been observed in muscles taken from obese NIDDM patients. These animals represent an excellent genetic model for studying insulin resistance and investigating the transition from insulin resistance in the absence of hyperinsulinemia to insulin resistance with hyperinsulinemia.

Pioglitazone-reduced insulin resistance in patient with Werner syndrome

Werner syndrome is a rare disorder that has provided a useful model for the study of human ageing. Patients with Werner syndrome usually display an aged appearance with various features including loss of hair, cataracts, atrophy of skin and peripheral fat, and diabetes. Mutations in the DNA helicase gene have been shown to be responsible for this disorder. One common feature of Werner syndrome is insulin resistance. However, as is the case in most patients with non-insulin-dependent diabetes mellitus (NIDDM), the precise mechanism underlying the disease is not known. As a step toward understanding the molecular mechanism of insulin resistance in Werner syndrome, we used pioglitazone, a new antidiabetic drug classified as a thiazolidinedione derivative, in a patient with Werner syndrome. Thiazolidinediones improve hyperglycaemia by enhancing insulin sensitivity without stimulating insulin secretion. These drugs have been shown to bind peroxisome proliferator-activated receptor (PPAR ), a dominant activator of fat-cell differentiation. This receptor is likely to mediate the antidiabetic effects of thiazolidinediones, since their affinity to PPAR correlates well with the strength of their effect as insulin sensitisers. A 53-year-old man with Werner syndrome was admitted for glycaemic control. The diagnosis was based on his clinical features and the reduced life-span of cultured fibroblasts. Although he was thin (body-mass index 14·2 kg/m) and had only a small amount of subcutaneous fat (%fat 4·9%), he had a moderate degree of insulin resistance as judged by the exogenous glucose infusion rate (GIR) during euglycaemic hyperinsulinaemic clamp (3·7 mg/kg per min, normal value 10·5 [SD 2·2]). His glycaemia was poorly controlled with a sulfonylurea agent, gliclazide. Written informed consent was obtained and the study was approved by the Institutional Ethical Committee. After 1 week of treatment by dietary restriction alone, pioglitazone 30 mg daily was initiated. After 12 weeks, the GIR had improved to 5·2 mg/kg per min (figure). This effect on the insulin sensitivity was similar to those observed in obese NIDDM patients; according to our data, the average GIR values for NIDDM patients (body-mass index 23 [SD 1·8]%, HbA1c 8·4 [1·4]%) before and after pioglitazone treatment was 8·2 [2·2] and 9·2 [2·0] mg/kg per min, respectively [p=0·003]; Kawamori R, Yamasaki Y, unpublished data). After 12 weeks of pioglitazone treatment, the patient’s fasting plasma glucose had decreased from 187 mg/dL (10·4 mmol/L) to 105 mg/dL (5·8 mmol/L) and glycated haemoglobin from 8·3% to 7·8%. All these glycaemic values deteriorated immediately after discontinuation of pioglitazone (figure). The fasting plasma insulin remained unchanged. These results suggest that pioglitazone was effective in ameliorating impaired insulin sensitivity and thus improved the glycaemic control in our patient. Recently, it was suggested that thiazolidinedione derivatives have direct effects on some tissues other than the adipose tissue, which has been considered to be the target organ of thiazolidinedione derivatives. Among the two isoforms of PPAR , PPAR 1, and PPAR 2, which can be activated to the same extent by a thiazolidinedione derivative, PPAR 1 (and maybe PPAR 2 also) seems to be weakly expressed in skeletal muscle. Also, a weak expression of PPAR 1 can be observed in liver, which seems to increase glucose uptake in response to pioglitazone. Thus, especially for this patient with Werner syndrome whose %fat was as low as 4·9%, the effects of pioglitazone on those non-adipose tissues may have had a role in improving the insulin sensitivity.

Very low calorie diet (VLCD): A useful alternative in the treatment of the obese NIDDM patient

Conventional treatment of obese noninsulin dependent diabetes mellitus (NIDDM) patients is often unsatisfactory. In this study the efficacy of Modifast ®, a commercial very low calorie diet (VLCD), was evaluated in a population of obese poorly controlled NIDDM patients. The mechanisms of action of VLCD in these patients were also studied by comparing: (i) Plasma insulin and glucose profiles after a VLCD and an isocaloric mixed meal and (ii) plasma amino acid levels, both at baseline and after four weeks of VLCD treatment. A total of 14 obese NIDDM patients ( M F 7 7 , median body mass index (BMI) 38.7 kg −2, interquartile range (IQ) 34.7–46.5 kg −2, waist circumference 116 cm, IQ 106–139 cm, insulin treated 7 14 ) with poor diabetic control (HbA 1c 8.6%, IQ 7.8–10%) were studied. Patients were given a VLCD (425 kcal/day) for 12 weeks. At baseline, VLCD and isocaloric meal tests were performed on consecutive mornings. Fasting plasma amino acid levels were also determined at baseline and after 4 weeks of VLCD treatment. Weight, waist circumference, HbA 1c, blood pressure, fasting plasma insulin, total cholesterol and triglyceride levels all fell significantly following VLCD treatment. Insulin therapy was able to be ceased in the seven insulin treated patients. Oral hypoglycaemic agent dosage fell from a median of eight (IQ 6–12) to two (IQ 0–8) tablets per day ( P = 0.03) in patients initially on this form of therapy. Insulin secretion was higher after VLCD than isocaloric meal ( P = 0.04). Fasting plasma alanine level fell from 512.0 (IQ 412.0–563.0) to 374.0 (IQ 342–472.0) μmol/l ( P = 0.04) following VLCD treatment. In conclusion, the short term use of a VLCD is very effective in rapidly improving glycaemic control and promoting substantial weight loss in obese NIDDM patients. Moreover, a VLCD diet increases insulin secretion and reduces substrate for gluconeogenesis. Thus, VLCD treatment may improve glycaemic control by factors more than caloric restriction alone.

Abnormalities of insulin pulsatility and glucose oscillations during meals in obese noninsulin-dependent diabetic patients: effects of weight reduction.

Twenty-seven obese patients, including 8 with normal glucose tolerance, 10 with subclinical NIDDM, and 9 with overt noninsulin-dependent diabetes mellitus (NIDDM), were studied before and after prolonged weight loss to assess the effects of the underlying defects of diabetes per se from those of obesity and chronic hyperglycemia on the regulation of pulsatile insulin secretion. Serial measurements of insulin secretion and plasma glucose were obtained during 3 standardized mixed meals consumed over 12 h. Insulin secretion rates were calculated by deconvoluting plasma C peptide levels using a mathematical model for C peptide clearance and kinetic parameters derived individually in each subject. Absolute (nadir to peak) and relative (fold increase above nadir) amplitudes of each insulin secretory pulse and glucose oscillation were calculated. Compared to the obese controls, the subclinical and overt NIDDM patients manifested the following abnormal responses: 1) decreased relative amplitudes of insulin pulses, 2) reduced frequency of glucose oscillations, 3) increased absolute amplitudes of glucose oscillations, 4) decreased temporal concomitance between peaks of insulin pulses and glucose oscillations, 5) reduced correlation between the relative amplitudes of glucose oscillations concomitant with insulin pulses, and 6) temporal disorganization of the insulin pulse profiles. These defects were more severe in the overt NIDDM patients, and weight loss only partially reversed these abnormalities in both NIDDM groups. These findings indicate that beta-cell responsiveness is reduced, and the regulation of insulin secretion is abnormal under physiological conditions in all patients with NIDDM, including those without clinical manifestations of the disease. These abnormalities are not completely normalized with weight loss, even in patients who achieve metabolic control comparable to that in obese controls. The results are consistent with the presence of an inherent beta-cell defect that contributes to secretory derangements in subclinical NIDDM patients. This abnormality precedes frank hyperglycemia and may ultimately contribute to the development of overt NIDDM.

Metformin: a new oral biguanide

The biguanide metformin is an oral anti-hyperglycemic agent used in the treatment of patients with non—insulin-dependent diabetes mellitus (NIDDM). Metformin is an important addition to the drug therapy options available for these patients because it reduces blood glucose levels predominantly by decreasing hepatic glucose production and release and also by increasing peripheral tissue sensitivity to insulin; it does not stimulate insulin secretion from the beta cells in the pancreas. Metformin also has a potentially beneficial effect by reducing serum lipid levels. Its glycemic control is similar to that of the sulfonylureas and is effective as monotherapy or in combination with sulfonylureas or insulin. Unlike sulfonylureas and insulin, it does not cause a gain in body weight, and when used as monotherapy, it does not cause hypoglycemia. The most common side effects associated with metformin are mild, transient, gastrointestinal symptoms, which are usually self-limiting. These side effects can be minimized by initiating metformin therapy at a low dose and gradually titrating upward, and by taking metformin with meals. Lactic acidosis caused by metformin is rare, and the risk of this complication may be diminished by the observance of prescribing precautions and contraindications that avoid accumulation of metformin or lactate in the body. In patients who are not getting the desired effect with sulfonylureas, it is useful to combine sulfonylureas with metformin therapy. Metformin should be considered a first-line agent, particularly in obese and/or hyperlipidemic NIDDM patients.

Effects of ingested fructose and infused glucagon on endogenous glucose production in obese NIDDM patients, obese non-diabetic subjects, and healthy subjects

Increased endogenous glucose production (EGP) and gluconeogenesis contribute to the pathogenesis of hyperglycaemia in non-insulin-dependent diabetes mellitus (NIDDM). In healthy subjects, however, EGP remains constant during administration of gluconeogenic precursors. This study was performed in order to determine whether administration of fructose increases EGP in obese NIDDM patients and obese non-diabetic subjects. Eight young healthy lean subjects, eight middle-aged obese NIDDM patients and seven middle-aged obese non-diabetic subjects were studied during hourly ingestion of 13C fructose (0.3 g.kg fat free mass-1.h-1) for 3 h. Fructose failed to increase EGP (measured with 6,6 2H glucose) in NIDDM (17.7 +/- 1.9 mumol.kg fat free mass-1.min-1 basal vs 15.9 +/- 0.9 after fructose), in obese non-diabetic subjects (12.1 +/- 0.5 basal vs 13.1 +/- 0.5 after fructose) and in lean healthy subjects (13.3 +/- 0.5 basal vs 13.8 +/- 0.6 after fructose) although 13C glucose synthesis contributed 73.2% of EGP in lean subjects, 62.6% in obese non-diabetic subjects, and 52.8% in obese NIDDM patients. Since glucagon may play an important role in the development of hyperglycaemia in NIDDM, healthy subjects were also studied during 13C fructose ingestion + hyperglucagonaemia (232 +/- 9 ng/l) and during hyperglucagonaemia alone. EGP increased by 19.8% with ingestion of fructose + glucagon (p < 0.05) but remained unchanged during administration of fructose or glucagon alone. The plasma 13C glucose enrichment was identical after fructose ingestion both with and without glucagon, indicating that the contribution of fructose gluconeogenesis to the glucose 6-phosphate pool was identical in these two conditions. We concluded that during fructose administration: 1) gluconeogenesis is increased, but EGP remains constant in NIDDM, obese non-diabetic, and lean individuals; 2) in lean individuals, both an increased glucagonaemia and an enhanced supply of gluconeogenic precursors are required to increase EGP; this increase in EGP occurs without changes in the relative proportion of glucose 6-phosphate production from fructose and from other sources (i.e. glycogenolysis + gluconeogenesis from non-fructose precursors).

Impaired Insulin-Induced Platelet Antiaggregating Effect in Obesity and In obese NIDDM Patients

To investigate the effects of insulin on platelets in obesity and in non-insulin-dependent diabetes mellitus (NIDDM)--classic insulin-resistant states--we determined ADP-induced platelet aggregation and platelet cGMP (guanosine 3',5'-cyclic monophosphate) content in platelet-rich plasma obtained from nine obese subjects and nine age-matched healthy volunteers and from eight NIDDM obese patients and nine age-matched healthy volunteers after a 3-min incubation with human recombinant insulin (0, 240, 480, 960, and 1,920 pmol/l). Platelet aggregation was evaluated using different ADP doses to measure the ADP concentration determined on the basis of a dose-response curve necessary to elicit a maximal aggregation of 50% (ED50). Insulin induced a dose-dependent decrease of platelet aggregation to ADP (P = 0.0001) in healthy subjects. A significant effect was evident starting from an insulin concentration of 240 pmol/l. On the contrary, in insulin-resistant subjects, insulin reduced platelet sensitivity to ADP only at a concentration of 1,920 pmol/l. When ADP ED50 values obtained in platelet-rich plasma incubated with insulin were expressed in percentage of the ADP ED50 values obtained in platelet-rich plasma without insulin, considered as 100%, we observed that ADP ED50 with 1,920 pmol/l insulin was 153.6 +/- 13.2% in the younger healthy subject group (P = 0.004), 150.0 +/- 3.8% in the older healthy subject group (P = 0.0001), 116.1 +/- 6.1% in obese subjects (P = 0.031), and 120.0 +/- 8.6% in NIDDM patients (P = 0.05). In healthy subjects, insulin induced a dose-dependent increase of platelet cGMP (P = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Contribution of obesity to insulin resistance in noninsulin-dependent diabetes mellitus.

Inasmuch as previous studies have obtained conflicting results on the contribution of obesity to insulin resistance in noninsulin-dependent diabetes mellitus (NIDDM), we studied 10 nonobese and 10 obese NIDDM patients with the isoglycemic-(approximately 10 mmol/L)-hyperinsulinemic clamp (two insulin infusions of 4 and 40 mU/m-2 min-1), combined with [3-3H]glucose infusion and indirect calorimetry. As compared with nonobese patients, obese NIDDM patients had higher baseline peripheral and estimated portal plasma insulin concentrations (113 +/- 18 vs. 46 +/- 3 pmol/L and 288 +/- 53 vs. 98 +/- 6 pmol/L, respectively; P < 0.05) and less suppressed endogenous insulin production during clamp. Hepatic glucose production was greater in obese than in nonobese patients (basal, 16 +/- 1.1 vs. 12 +/- 0.5 mumol/kg-1 fat-free mass (FFM) min-1; clamp, 5.7 +/- 0.5 vs. 2.8 +/- 0.2 mumol/kg-1 FFM min-1, P < 0.05). Glucose utilization increased to a lesser extent in obese than in nonobese patients (49 +/- 5 vs. 73 +/- 7 mumol/kg-1 FFM min-1, P < 0.05) during clamp because of a lower increase in nonoxidative glucose metabolism (30 +/- 5 vs. 50 +/- 7 mumol/kg-1 FFM min-1, P < 0.05). Plasma free fatty acid concentrations and rates of lipid oxidation were greater in obese (P < 0.05) patients and correlated with hepatic glucose production (r = 0.79 and 0.50, P < 0.05). In conclusion, obesity exaggerates hepatic as well as extra-hepatic insulin resistance in NIDDM. The impaired inhibition of pancreatic beta-cell function by exogenous insulin contributes to exaggerated hyperinsulinemia in obese NIDDM.

Absorption of Rapid-Acting Insulin in Obese and Nonobese NIDDM Patients

To study the absorption rate of rapid-acting insulin from subcutaneous injection sites in nonobese and obese non-insulin-dependent diabetes mellitus (NIDDM) patients. Ten nonobese and 10 obese NIDDM patients (body mass indexes 24.1 +/- 0.4 and 31.4 +/- 0.8 kg/m2, respectively) received four subcutaneous injections of 125I-labeled rapid-acting insulin (Actrapid Human, 5 U): three in the abdominal wall above, lateral to, and below the umbilicus; and one in the thigh. The depth of the subcutaneous fat layer was measured using ultrasound techniques. The residual radioactivity was monitored externally for 270 min. The disappearance half-life of 125I-insulin was between 4 and 6 h from all injection sites, with the exception of the upper abdominal area in the nonobese subjects, where it measured approximately 3 h. The residual radioactivity did not differ between nonobese and obese patients measured from any of the sites. In the nonobese group, the most rapid absorption of 125I-insulin was found from the upper abdominal area and the slowest from the thigh. In the obese group, the absorption rates did not differ between sites. No correlation was found between the depth of the fat layer and the residual radioactivity when measured at any site. Our results indicate that the absorption of rapid-acting insulin is markedly slow in both obese and nonobese NIDDM patients compared with IDDM patients and healthy subjects studied previously. In the nonobese group, the most rapid absorption of 125I-insulin is obtained after injection into the upper abdominal area. Inter- and intraregional differences are small in the obese patients. Consequently the choice of injection site is of little importance in this group.

Hypoxia stimulates glucose transport in insulin-resistant human skeletal muscle.

Insulin and muscle contraction stimulate glucose transport into muscle cells by separate signaling pathways, and hypoxia has been shown to operate via the contraction signaling pathway. To elucidate the mechanism of insulin resistance in human skeletal muscle, strips of rectus abdominis muscle from lean (body mass index [BMI] < 25), obese (BMI > 30), and obese non-insulin-dependent diabetes mellitus (NIDDM) (BMI > 30) patients were incubated under basal and insulin-, hypoxia-, and hypoxia + insulin-stimulated conditions. Insulin significantly stimulated 2-deoxyglucose transport approximately twofold in muscle from lean (P < 0.05) patients, but not in muscle from obese or obese NIDDM patients. Furthermore, maximally insulin-stimulated transport rates in muscle from obese and diabetic patients were significantly lower than rates in muscle from lean patients (P < 0.05). Hypoxia significantly stimulated glucose transport in muscle from lean and obese patients. There were no significant differences in hypoxia-stimulated glucose transport rates among lean, obese, and obese NIDDM groups. Hypoxia + insulin significantly stimulated glucose transport in lean, obese, and diabetic muscle. The results of the present study suggest that the glucose transport effector system is intact in diabetic human muscle when stimulated by hypoxia.

Daily Walking Combined With Diet Therapy Is a Useful Means for Obese NIDDM Patients Not Only to Reduce Body Weight But Also to Improve Insulin Sensitivity

To evaluate the effects of walking combined with diet therapy (1,000-1,600 kcal/day) on insulin sensitivity in obese non-insulin-dependent diabetes mellitus (NIDDM) patients. Subjects were divided into two groups: 10 patients were managed by diet alone (group D), and 14 patients were placed in the diet and exercise group (group DE). Group DE was instructed to walk at least 10,000 steps/day on a flat field as monitored by pedometer (19,200 +/- 2,100 steps/day), and group D was told to maintain a normal daily routine (4,500 +/- 290 steps/day). A glucose clamp procedure at an insulin infusion rate of 40 microU.min-2.min-1 was performed before and after the 6- to 8-week training program. Mean serum insulin concentrations ranged from 720 to 790 pmol/l. While body weight (BW) in groups D and DE decreased significantly (P < 0.01) during the study, the amount of BW reduction in group DE was greater than that in group D (7.8 +/- 0.8 vs. 4.2 +/- 0.5 kg, P < 0.01). After training, glucose infusion rate (GIR) and metabolic clearance rate (MCR) in group D did not significantly increase; however, GIR and MCR increased significantly in group DE, from 17.21 +/- 1.11 to 26.09 +/- 1.11 mumol.kg-1.min-1 (P < 0.001) and from 3.0 +/- 0.3 to 5.3 +/- 0.4 ml.kg-1.min-1 (P < 0.001), respectively. The analysis of variance showed significant effects of exercise (time x exercise, P = 0.0005) for the improvement of MCR. Significant correlations were also observed between delta MCR and average steps per day (r = 0.7257, P < 0.005) in group DE. Walking, which can be safely performed and easily incorporated into daily life, can be recommended as an adjunct therapy to diet treatment in obese NIDDM patients, not only for BW reduction, but also for improvement of insulin sensitivity.

Glucose Metabolism During the Starved-To-Fed Transition in Obese Patients With NIDDM

To analyze the effects of short-term fasting on postprandial glucose metabolism in non-insulin-dependent diabetes mellitus (NIDDM), two groups of nine obese NIDDM patients and two comparable groups of control subjects underwent a 5-h oral glucose tolerance test after either 14 h or 4 days of fasting. The fluxes and the rates of oxidation and storage of glucose were measured using a dual isotope technique combined with indirect calorimetry. The effect of fasting on insulin action and beta-cell responsiveness was tested in an additional group of six obese NIDDM patients with a euglycemic hyperinsulinemic clamp followed by an intravenous glucagon test. In the diabetic patients, fasting enhanced beta-cell response to glucose and glucagon and did not modify insulin action. This response differs from that of nondiabetic subjects in whom fasting is known to impair insulin secretion and action. Regarding glucose fluxes, it was observed that in the overnight-fasted state, the incremental tissular disposal following glucose ingestion was reduced by approximately 50% in the diabetic versus control subjects in relation to an approximately 62% impairment in glucose storage. After fasting, incremental tissular disposal was restored to normal, glucose oxidation was virtually abolished, and storage was increased approximately threefold. Thus, in NIDDM patients, fasting corrects the defect in glycogen storage without modifying the action of insulin on glucose uptake and improves beta-cell responsiveness, the latter two effects being opposite to those observed in nondiabetic subjects.

Obstructive sleep apnea in obese noninsulin-dependent diabetic patients: effect of continuous positive airway pressure treatment on insulin responsiveness.

Patients with noninsulin-dependent diabetes mellitus (NIDDM) are often obese and frequently complain of tiredness. These features are also characteristically seen in patients with obstructive sleep apnea (OSA). Therefore, it was the aim of this study to assess the prevalence of OSA among a group of obese NIDDM patients who have some clinical features of OSA. The effect of reversal of OSA by nasal continuous positive airway pressure (CPAP) treatment on insulin responsiveness was also investigated. From a population of 179 NIDDM patients with a body mass index (BMI) greater than 35 kg/m2, we performed ambulatory sleep monitoring on 31 (15 males and 16 females) who admitted to either heavy snoring or excessive sleepiness. Results were reviewed by a sleep physician blinded to the clinical status of the patients, and 22 (70%) were found to have moderate or severe OSA, with mean oxygen desaturation indexes of 10.3 +/- 5.3 and 30.7 +/- 13.2 episodes/h, respectively. A subgroup of 10 patients (seven males and three females) with a mean BMI of 42.7 +/- 4.3 kg/m2 was treated with nightly CPAP for 4 months. These subjects all had significant OSA, with frequent obstructive apneas (mean, 47 +/- 31.6 episodes/h) and oxygen desaturation (mean minimum O2 saturation, 74 +/- 9.5%), as determined by polysomnography. One patient was excluded from analysis because of infrequent use of CPAP. Insulin responsiveness in terms of glucose disposal measured by hyperinsulinemic euglycemic clamps improved from 11.4 +/- 6.2 to 15.1 +/- 4.6 mumol/kg.min (P < 0.05) during CPAP treatment. These results indicate that OSA occurs commonly in obese NIDDM patients with excessive sleepiness or heavy snoring. Treatment of their OSA may improve insulin responsiveness.

ApoA-IV polymorphism associated with myocardial infarction in obese NIDDM patients. The San Luis Valley Diabetes Study.

Non-insulin-dependent diabetes mellitus (NIDDM) confers myocardial infarction (MI) risk unexplained by known factors. In 356 NIDDM patients and 1,087 people with normal glucose tolerance, we investigated the association between MI risk and polymorphism at codon 360 in the apolipoprotein A-IV (apoA-IV) gene. During 1984-1992, MI was diagnosed in 84 diabetic and in 106 nondiabetic people. The risk of MI did not differ by apoA-IV phenotype in nondiabetic people; however, in NIDDM patients, those with the apoA-IV 1-2 phenotype had 2.8 (95% confidence interval: 1.4-5.6) higher MI risk than those with the 1-1 phenotype, adjusting for age, gender, ethnicity, hypertension, smoking, body mass index, fat centrality, and low-density lipoprotein and high-density lipoprotein cholesterol. The risk of MI was particularly high in obese NIDDM patients with the apoA-IV 1-2 phenotype: 5.1 (2.4-11.2) times that in obese apoA-IV 1-1 NIDDM patients and 7.7 (3.6-16.7) times that in lean nondiabetic people. The effect of apoA-IV 1-2 did not appear to be a part of the insulin-resistance syndrome nor was it dependent on diabetes duration or control. One half of the excess MI risk in the diabetic population studied was explained by the apoA-IV 1-2 phenotype. These results indicate that approximately 17% of NIDDM patients have a high MI risk apoA-IV phenotype that is particularly deleterious in obese patients.

Effects of glucose and amino acid infusion on glucose turnover in insulin-resistant obese and type II diabetic patients

Glucose turnover was assessed from [6,6- 2H]glucose and [U- 13C]glucose dilution analysis in six lean nondiabetic subjects, six obese patients with normal glucose tolerance, and six obese patients with non-insulin-dependent diabetes mellitus (NIDDM) during sequential infusions of glucose (13.9 μmol/kg fat-free mass [FFM]/min) and glucose + amino acid (4.2 mg/kg FFM/min). Cori cycle activity was assessed from the difference between glucose turnover obtained from [6,6- 2H]glucose and [U- 13C]glucose. During infusion of glucose alone, total glucose turnover was increased by 70% in obese NIDDM patients. Amino acid infusion decreased glucose concentrations by 0.8, 0.5, and 1.8 mmol/L in controls, obese patients, and NIDDM patients, respectively. This decrease in glycemia occurred despite an increase in glucose turnover in lean and obese nondiabetic subjects, and was due to an increased metabolic clearance rate (MCR) of glucose. In NIDDM patients the MCR of glucose was unchanged, and the decrease in glycemia was explained by a diminution in hepatic glucose output. Glucose turnover obtained by [6.6- 2H]dilution analysis exceeded significantly the values obtained by 13C dilution analysis in obese subjects and obese NIDDM patients, but not in controls. This indicates an increased Cori cycle activity in these patients.

Effect of NIDDM on the kinetics of whole-body protein metabolism.

We postulated that dietary protein utilization and body protein metabolism are altered in hyperglycemic individuals with non-insulin-dependent diabetes mellitus (NIDDM). This was tested by estimating the kinetics of protein metabolism in obese NIDDM patients in the hyperglycemic state of isoenergetic feeding and in the normoglycemic state induced by the prolonged use of a very-low-energy diet (VLED) and comparing them with results in obese nondiabetic subjects studied previously. Seven obese subjects with NIDDM (one male, six females, body mass index = 35.8 +/- 2.0 kg/m2) were given a 1.7 MJ (410 kcal) all protein (93 g/day) diet derived from hydrolyzed collagen and supplemented with tryptophan and methionine, which provides 16% of its amino acids as essential, a multivitamin and mineral supplement, and 16 mmol KCl for 42 days. During the seven-day isoenergetic diet and at weeks 4 and 6 of the VLED, amino nitrogen (N) flux rate was calculated from the urine [15N]urea enrichment by using the 60-h oral [15N]glycine method to obtain the integrated feeding-fasting metabolism. Rates of synthesis (S) and breakdown (B) were calculated from N flux. At day 7 of the isoenergetic diet, whole-body N flux, S, B, and resting metabolic rate (RMR) were 12-24% greater (P < 0.05) in the NIDDM subjects than observed in nondiabetic obese subjects. Mean plasma glucose decreased (P < 0.05) from the isoenergetic period (14.9 +/- 2.4 mM) to 7.2 +/- 1.2 mM at week 4 and 6.5 +/- 1.1 mM at week 6 of the VLED. RMR declined progressively by 25% at week 5 of the VLED. Corresponding significant (P < 0.05) decreases from isoenergetic feeding to weeks 4 and 6 of the VLED occurred in whole-body N flux (from 51 +/- 2 to 42 +/- 1 g N/day), in S (from 38 +/- 3 to 24 +/- 1 g N/day), and in B (from 39 +/- 3 to 26 +/- 1 g N/day) resulting in net losses (S-B). S-B was significantly more negative (P < 0.05) in NIDDM than in the nondiabetic obese subjects at week 4 (-1.5 +/- 0.5 vs. 0.9 +/- 0.3 g N/day) but not at week 6 (-1.3 +/- 0.4 vs. -0.9 +/- 4 g N/day). During the VLED, N balance became less negative with time but never reached equilibrium in NIDDM. Thus, abnormal protein metabolism is present in NIDDM in the isoenergetic fed state with moderate hyperglycemia and persists during a VLED that restores glycemia to near normal.

Relationship between insulin receptor tyrosine kinase activity and internalization in monocytes of non-insulin-dependent diabetes mellitus patients

Reduced insulin receptor tyrosine kinase activity and internalization have been reported in non-insulin-dependent diabetes mellitus (NIDDM) patients. To clarify whether in NIDDM the defective internalization is caused by the defective kinase activity, we studied receptor tyrosine kinase activity and internalization in monocytes from eight lean control and six obese subjects and 10 obese NIDDM patients. Receptor internalization was also stimulated by an anti-insulin receptor antibody (MA-10) that is unable to stimulate receptor kinase activity. Basal exogenous tyrosine kinase activity was not different in monocytes from the three groups of subjects. As compared with control subjects (2,690 ± 637 fmol 32P incorporated), insulin (100 nmol/L)-stimulated tyrosine kinase activity was lower in NIDDM patients (1,262 ± 318, P < .05), but not in obese subjects (2,640 ± 731). Basal receptor autophosphorylation did not differ between the three groups, whereas insulin-stimulated autophosphorylation in comparison to that in control subjects was reduced in NIDDM patients ( P < .05), but not in obese subjects. In NIDDM patients, receptor internalization induced by both insulin and MA-10, was lower ( P < .05) than that in control and obese subjects. No correlation was found between receptor internalization and exogenous tyrosine kinase activity ( r = .30, NS) or autophosphorylation ( r = .08, NS). Our study demonstrates the coexistence of both reduced insulin receptor tyrosine kinase activity and internalization in monocytes from NIDDM patients, but does not suggest that the two defects are linked by a cause-effect relationship, because (1) in NIDDM a significant reduction of receptor internalization is also observed with MA-10, a ligand that does not activate receptor kinase activity; and (2) looking at individual data, receptor internalization is not correlated to receptor kinase activity.