Non-insulin-dependent Diabetes Mellitus Subjects Research Articles

Impact of Intensive Educational Approach to Dietary Change in NIDDM

The aim of this study was to compare the effects of an intensive educational approach incorporating longer time, greater simplicity, repetition, and cognitive motivational techniques with a conventional one in subjects with established non-insulin-dependent diabetes mellitus (NIDDM) whose weight, glycemic control, and diet were not optimal. Subjects were randomly allocated to intensive or conventional education. Of 350 subjects, 70 met the study criteria, which included established NIDDM (greater than or equal to 3 mo), suboptimal recent glycemic control, dietary fat intake greater than or equal to 35% of total energy intake, and body mass index greater than or equal to 25 kg/m2. The intensive approach was associated with significantly greater improvements in dietary compliance, dietary intake (complex carbohydrate, [P = 0.013], legumes [P less than 0.0001], fiber [P less than 0.0001], total fat [P less than 0.004], saturated fat [P less than 0.004]), and total cholesterol level (P = 0.007). The transient improvement in glycemic control was similar in both groups. An intensive education program can improve dietary compliance in established NIDDM subjects more than a conventional one. These recommended dietary improvements achieve better improvement in total cholesterol but do not necessarily improve glycemic control.

Effects of Meal Ingestion on Plasma Amylin Concentration in NIDDM and Nondiabetic Humans

Recent interest has focused on the potential role of amylin in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM). This 37-amino acid peptide is found in extracellular amyloid deposits in approximately 50% of pancreatic islets of patients with NIDDM and has been shown to inhibit skeletal muscle glycogen synthesis in vitro. Immunocytochemical studies have colocalized amylin and insulin within beta-cell secretory granules in nondiabetic humans, provoking the following questions. Is amylin cosecreted with insulin? Are circulating amylin concentrations higher in patients with NIDDM either before or after food ingestion? To answer these questions, we developed a sensitive and specific immunoassay to measure plasma concentrations of amylin in humans. Use of this assay indicated that, in lean nondiabetic subjects, glucose ingestion resulted in an increase (P less than 0.001) in the plasma concentration of amylin (from 2.03 +/- 0.22 to 3.78 +/- 0.39 pM) and insulin (from 48.3 +/- 3.1 to 265 +/- 44 pM). There was a significant correlation between the concentrations of insulin and amylin (r = 0.74, P less than 0.001) and the increase in insulin and amylin concentration (r = 0.65, P less than 0.005). Fasting concentrations of amylin did not differ in diabetic and weight-matched nondiabetic subjects and showed a similar pattern of change after ingestion of a mixed meal. We conclude that amylin is secreted in response to ingestion of either glucose or a mixed meal and circulates at concentrations that do not differ in patients with NIDDM and nondiabetic subjects. It remains to be determined whether amylin at physiological concentrations influences carbohydrate metabolism and if so whether its effects differ in diabetic and nondiabetic humans.

Salt-sensitive blood pressure and exaggerated vascular reactivity in the hypertension of diabetes mellitus

purpose: This study evaluates the effects of dietary salt restriction and loading on blood pressure in normotensive and hypertensive patients with non-insulin-dependent diabetes mellitus (NIDDM). Salt sensitivity of blood pressure responses is compared to vascular reactivity to infused angiotensin II on the two sodium diets. patients and methods: We studied 19 patients with NIDDM (seven normotensive, 12 hypertensive) and seven nondiabetic control subjects under metabolic balance after 6 days on a constant low-(20 mEq) sodium diet and again after 6 days on a high- (250 mEq) sodium diet. Salt sensitivity of blood pressure was determined by the increment in integrated 24-hour blood pressure values on changing from the low- to the high-sodium diet. Blood pressure and plasma aldosterone responses to a graded-dose infusion of angiotensin II were also examined on both sodium diets. results: Eight of 12 hypertensive patients with NIDDM displayed salt-sensitive blood pressure responses, whereas none of the normotensive patients with NIDDM or control subjects were salt-sensitive. Patients with NIDDM also had augmented blood pressure responses to infused angiotensin II on both sodium diets when compared to control subjects. Whereas controls had reduced vascular responses to angiotensin II on the low-sodium diet, these responses were not decreased in patients with NIDDM. Patients with NIDDM also retained more sodium on the high-sodium diet than did the control subjects. conclusion: Hypertension in patients with NIDDM is frequently salt-sensitive, which may be due to sodium retention and enhanced vascular reactivity to angiotensin II. Since sodium restriction does not normally reduce vascular reactivity to angiotensin II in NIDDM, salt-restricted diets may be less effective in blood pressure control in hypertensive NIDDM.

Insulin-Receptor Autophosphorylation and Endogenous Substrate Phosphorylation in Human Adipocytes From Control, Obese, and NIDDM Subjects

We identified a possible endogenous substrate (pp185) of the insulin-receptor kinase in human adipocytes by treating intact cells with insulin and immunoblotting the cellular extracts with polyclonal antiphosphotyrosine antibody. This 185,000-Mr protein was phosphorylated on tyrosine residues in response to insulin in both rat and human adipocytes. The time course of pp185 phosphorylation at 37 degrees C was rapid and corresponded closely to insulin-receptor autophosphorylation but preceded insulin-stimulated glucose transport. Unlike many growth factor receptors, including the insulin receptor, pp185 was not adsorbed to wheat-germ agglutinin. We found that pp185 phosphorylation occurred at 12 degrees C and that the phosphoprotein was associated with both cytoplasmic and membrane fractions at this temperature. Furthermore, pp185 phosphorylation was induced to the same extent as insulin by vanadate and hydrogen peroxide, compounds previously shown to mimic the biologic effects of insulin. In addition, dose-response analysis of insulin-stimulated glucose transport, receptor autophosphorylation, and pp185 phosphorylation resulted in ED50 values of 0.3, 12, and 12 ng/ml, respectively. These results demonstrate the magnitude of "spare" autophosphorylation and pp185 phosphorylation with respect to glucose transport stimulation in human adipocytes. To determine whether the insulin resistance characteristic of non-insulin-dependent diabetes mellitus (NIDDM) and obesity is associated with a defect in receptor autophosphorylation and/or endogenous substrate phosphorylation, we estimated the extent of beta-subunit and pp185 phosphorylation in adipocytes from NIDDM, obese, and healthy subjects. Although the efficiency of coupling between receptor activation and pp185 phosphorylation was normal in obesity and NIDDM, the capacity for insulin-receptor autophosphorylation was approximately 50% lower in NIDDM subjects compared with nondiabetic obese or lean subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Contribution of Impaired Muscle Glucose Clearance to Reduced Postabsorptive Systemic Glucose Clearance in NIDDM

The reduced postabsorptive rates of systemic glucose clearance in non-insulin-dependent diabetes mellitus (NIDDM) are thought to be the consequence of insulin resistance in peripheral tissues. Although the peripheral tissues involved have not been identified, it is generally assumed to be primarily muscle, the major site of insulin-mediated glucose disposal. To test this hypothesis, we measured postabsorptive systemic and forearm glucose utilization and clearance in 15 volunteers with NIDDM and 15 age- and weight-matched nondiabetic volunteers. Although systemic glucose utilization was increased in NIDDM subjects (14.5 +/- 0.5 vs. 11.2 +/- 0.2 mumol.kg-1.min-1, P less than 0.001), systemic glucose clearance was reduced 1.40 +/- 0.06 vs. 2.13 +/- 0.05 ml.kg-1.min-1, P less than 0.01). Although forearm glucose utilization was increased in NIDDM subjects (0.663 +/- 0.058 vs. 0.411 +/- 0.019 mumol.dl-1.min-1, P less than 0.001), forearm glucose dl-1 clearance was reduced (0.628 +/- 0.044 vs. 0.774 +/- 0.037 ml.L-1.min-1, P less than 0.01). However, extrapolation of forearm data to total-body muscle indicated that impaired clearance reduced muscle glucose disposal by only 61 +/- 21 mumol/min, whereas impaired systemic clearance reduced systemic glucose disposal by 662 +/- 82 mumol/min. Thus, impaired muscle glucose clearance accounted for less than 10% of the reduced systemic glucose clearance in NIDDM subjects. Therefore, we conclude that muscle insulin resistance plays only a minor role in the reduced systemic glucose clearance found in NIDDM in the postabsorptive state and propose that reduced brain glucose clearance is largely responsible.

Intracellular glucose oxidation and glycogen synthase activity are reduced in non-insulin-dependent (type II) diabetes independent of impaired glucose uptake.

To examine whether reduced rates of oxidative (Gox) and non-oxidative (Nox) glucose metabolism in non-insulin-dependent diabetes mellitus (NIDDM) are due to reduced glucose uptake, intrinsic defects in intracellular glucose metabolism or increased fat oxidation (Fox), indirect calorimetry was performed at similar glucose uptake rates in eight nonobese NIDDM and eight comparable nondiabetic subjects. Three glucose clamp studies were performed: one in the nondiabetic and two in the NIDDM subjects. In the nondiabetic subjects, glucose uptake was increased to 7.62 +/- 0.62 mg/kg of fat-free mass (FFM) per min by increasing serum insulin to 309 pmol/liter at a glucose concentration of 5.1 mmol/liter. By raising the concentration of either serum glucose or insulin fourfold in the NIDDM subjects, glucose uptake was matched to nondiabetic subjects (8.62 +/- 0.49 and 8.59 +/- 0.51 mg/kg FFM per min, respectively, P = NS). Skeletal muscle glycogen synthase activity and plasma lactate levels were measured to characterize Nox. When glucose uptake was matched to nondiabetics by hyperglycemia or hyperinsulinemia, Gox was reduced by 26-28% in NIDDM (P less than 0.025) whereas Fox was similar. Nox was greater in NIDDM (P less than 0.01) and was accompanied by increases in circulating lactate levels. Glycogen synthase activity was reduced by 41% (P less than 0.025) when glucose uptake was matched by hyperglycemia. Glycogen synthase activity was normalized in NIDDM, however, when glucose uptake was matched by hyperinsulinemia. Therefore, a defect in Gox exists in nonobese NIDDM subjects which cannot be overcome by increasing glucose uptake or insulin. Since both glucose uptake and Fox were similar in the two subject groups these factors were not responsible for reduced Gox. Increased Nox in NIDDM is primarily into lactate. Reduced glycogen synthase activity in NIDDM is independent of glucose uptake but can be overcome by increasing the insulin concentration.

Evaluation and clinical applications of measurement of urinary growth hormone in diabetic subjects.

Quantities of growth hormone (GH) excreted into the urine over 24 h were measured by the highly sensitive sandwich enzyme immunoassay in 63 non-insulin-dependent diabetes mellitus (NIDDM) subjects, 6 insulin-dependent diabetes mellitus (IDDM) subjects, and 17 age-matched nondiabetic control subjects. GH-provocative tests with intravenous infusion of arginine revealed that urinary GH levels are closely correlated with the integrated concentrations of serum GH (r = .931, n = 14, P less than .001). Furthermore, 24-h urinary GH in control and diabetic subjects was inversely related to body mass index (r = .359, n = 80, P less than .001). The mean 24-h urinary GH in NIDDM subjects was 11.1 +/- 1.9 ng/g creatinine (Cr), which was not significantly different from that in nondiabetic control subjects (9.2 +/- 2.7 ng/g Cr). By contrast, the individual values for IDDM subjects varied widely, and their mean values (42.5 +/- 20.8 ng/g Cr) were much greater than those in the control and NIDDM subjects (P less than .01). The degree of glycemic control does not seem to affect 24-h urinary GH in NIDDM. The mean 24-h urinary GH in 7 subjects with proliferative diabetic retinopathy was comparable to that in subjects without retinopathy or with background retinopathy. Thus, the measurement of 24-h urinary GH appears to provide reliable assessments of endogenous GH secretion under physiological conditions and will be a useful tool for obtaining further insight into the role of GH in diabetes.

Fasting Plus Prandial Insulin Supplements Improve Insulin Secretory Ability in NIDDM Subjects

To examine how insulin secretory ability is modified by strict glycemic control in non-insulin-dependent diabetes mellitus (NIDDM) subjects, basal and/or prandial insulin was supplemented for 4 wk in 24 diabetic subjects who were secondary failures to sulfonylurea treatment. One intermediate-acting insulin injection a day (n = 7) failed to suppress the rise in plasma C-peptide after meals and did not improve plasma C-peptide responses during a posttreatment oral glucose challenge. Continuous subcutaneous insulin infusion with a premeal bolus (n = 8) suppressed both fasting and meal-related rises in C-peptide and improved C-peptide response during the posttreatment oral glucose challenge. Daily insulin requirements during the 4 wk of treatment were reduced significantly by 52%. A short-acting insulin injection before each meal (n = 9) without basal supplementation suppressed the prandial rise in C-peptide and was associated with a significant reduction in daily insulin requirements during 4 wk of treatment by 28%. Diabetic subjects whose fasting and prandial hyperglycemia were less than 140 and less than 200 mg/dl, respectively, showed a significantly higher C-peptide response during oral glucose challenge after treatment than those whose insulin treatment only normalized (less than 200 mg/dl) prandial but not basal hyperglycemia (greater than 140 mg/dl). These results suggest that a short-term period of meal-related insulin treatment (which normalized prandial glycemia) increases residual beta-cell function in NIDDM subjects who failed long-term sulfonylurea administration. A basal insulin supplement alone was not effective. The effectiveness of a prandial insulin supplement may have been further improved by a combined basal and meal-related treatment program.

Metabolic effects of adding sucrose and aspartame to the diet of subjects with noninsulin-dependent diabetes mellitus

This study compared the effects of adding sucrose and aspartame to the usual diet of individuals with well-controlled noninsulin-dependent diabetes mellitus (NIDDM). A double-blind, cross-over design was used with each 6-wk study period. During the sucrose period, 45 g sucrose (9% of total daily energy) was added, 10 g with each main meal and 5 g with each between-meal beverage. An equivalent sweetening quantity of aspartame (162 mg) was ingested during the aspartame period. The addition of sucrose did not have a deleterious effect on glycemic control, lipids, glucose tolerance, or insulin action. No differences were observed between sucrose and aspartame. Sucrose added as an integral part of the diabetic diet does not adversely affect metabolic control in well-controlled NIDDM subjects. Aspartame is an acceptable sugar substitute for diabetic individuals but no specific advantage over sucrose was demonstrated.

Adrenal Medullary Fibrosis in IDDM of Long Duration

We conducted a retrospective pathology study to determine whether subjects with long-standing insulin-dependent diabetes mellitus (IDDM) have abnormalities of the adrenal medulla compared with subjects with non-insulin-dependent diabetes mellitus (NIDDM) and nondiabetic individuals. Slides were scored from 0 (no fibrosis) to 3+ (complete fibrosis). Nineteen IDDM subjects aged 30-60 yr (mean +/- SE 44.9 +/- 2.5 yr) at autopsy and with duration of diabetes 13-45 yr (26.8 +/- 1.8 yr) were studied. Twelve NIDDM subjects aged 61-84 yr (73.3 +/- 2.5 yr) with duration of diabetes 17-33 yr (22.8 +/- 1.9 yr) were studied. Twenty-two nondiabetic subjects aged 32-77 yr (53.7 +/- 2.9 yr) were studied. Four of 19 (27%) IDDM subjects had moderate to severe fibrosis compared to 1 of 12 (8.3%) NIDDM subjects and 1 of 22 (4.5%) control subjects. Thirteen of 19 (68%) IDDM subjects had a score of 1, 2, or 3 compared to 3 of 22 (13.6%) control subjects (P less than .0005). There was an association between duration of IDDM and fibrosis score (r = .46, P less than .05) and between age and fibrosis score among IDDM subjects (r = .57, P = .01). No association between age or duration of diabetes and fibrosis score was observed for NIDDM or control subjects. Adrenal medullary fibrosis may be an anatomical correlate of the diminished epinephrine secretion that occurs in response to insulin-induced hypoglycemia in some IDDM subjects.

Intestinal glucose and amino acid absorption in healthy volunteers and noninsulin-dependent diabetic subjects

Reducing the rate of glucose absorption is a useful approach to the treatment of noninsulin-dependent diabetes mellitus (NIDDM). Intestinal absorption of glucose and amino acids is known to be increased in diabetes in laboratory animals but has not been systematically studied in human NIDDM subjects. In this study the intestinal absorption of glucose and glycine was measured during steady-state perfusion of the jejunum in 10 NIDDM subjects and in 11 healthy volunteers. Absorption rates were linearly related to solute load for both glucose and glycine. Over the range of solute concentrations, absorption rates of glucose (F = 4.38, p less than 0.05) and glycine (F = 7.07, p less than 0.02) were slightly reduced in diabetic subjects. The reduction in absorption rates may be accounted for by differences in age and diet between the groups. It is concluded that glucose and amino acid absorption is not increased in human NIDDM.

Predominant role of gluconeogenesis in increased hepatic glucose production in NIDDM.

Excessive hepatic glucose output is an important factor in the fasting hyperglycemia of non-insulin-dependent diabetes mellitus (NIDDM). To determine the relative contributions of gluconeogenesis and glycogenolysis in a quantitative manner, we applied a new isotopic approach, using infusions of [6-3H]glucose and [2-14C]acetate to trace overall hepatic glucose output and phosphoenolpyruvate gluconeogenesis in 14 postabsorptive NIDDM subjects and in 9 nondiabetic volunteers of similar age and weight. Overall hepatic glucose output was increased nearly twofold in the NIDDM subjects (22.7 +/- 1.0 vs. 12.0 +/- 0.6 mumol.kg-1.min-1 in the nondiabetic volunteers, P less than .001); phosphoenolpyruvate gluconeogenesis was increased more than threefold in the NIDDM subjects (12.7 +/- 1.4 vs. 3.6 +/- 0.4 mumol.kg-1.min-1 in the nondiabetic subjects, P less than .001) and was accompanied by increased plasma lactate, alanine, and glucagon concentrations (all P less than .05). The increased phosphoenolpyruvate gluconeogenesis accounted for 89 +/- 6% of the increase in overall hepatic glucose output in the NIDDM subjects and was significantly correlated with the fasting plasma glucose concentrations (r = .67, P less than .01). Glycogenolysis, calculated as the difference between overall hepatic glucose output and phosphoenolpyruvate gluconeogenesis, was not significantly different in the NIDDM subjects (9.9 +/- 0.06 mumol.kg-1.min-1) and the nondiabetic volunteers (8.4 +/- 0.3 mumol.kg-1.min-1). We conclude that increased gluconeogenesis is the predominant mechanism responsible for increased hepatic glucose output in NIDDM.

Maleness as risk factor for slowly progressive IDDM.

The effect of sex on longitudinal changes in serum C-peptide immunoreactivity (CPR) response to the oral glucose tolerance test (OGTT) was examined up to 48 mo in 30 islet cell antibody-positive (ICA+), non-insulin-dependent diabetes mellitus (NIDDM) subjects (15 men, 15 women) who were matched for age, duration of diabetes, and mode of treatment. The subjects were recruited from 2858 NIDDM patients screened for ICA between 1980 and 1984. In male NIDDM subjects, CPR levels to OGTT decreased insidiously, and 8 of 15 men developed the insulin-dependent state with abolished CPR. Only 2 female NIDDM subjects progressed to the insulin-dependent state (P less than .05, women vs. men). Thus, CPR in female subjects tended to decrease less than in male subjects. There were no significant differences between the two groups in human leukocyte antigens (HLA) or titer of ICA during the follow-up period. These results suggest that maleness is a major risk factor for slowly progressive beta-cell dysfunction in adult-onset insulin-dependent diabetes mellitus (IDDM).

Assessment of the postprandial pattern of glucose metabolism in nondiabetic subjects and patients with non-insulin-dependent diabetes mellitus using a simultaneous infusion of [2 3H] and [3 3H] glucose

Glucose turnover determined with tritiated isotopes of glucose is subject to potential error due to glucose/glucose-6-phosphate cycling and/or cycling through glycogen. To determine the extent to which these processes alter the apparent pattern of postprandial glucose metabolism, we measured glucose turnover simultaneously with [2 3H] glucose (an isotope that minimally cycles through glycogen but is extensively detritiated during glucose/glucose-6-phosphate cycling) and [3 3H] glucose (an isotope that is not detritiated during glucose/glucose-6-phosphate cycling but can cycle through glycogen). Glucose turnover was measured in patients with non-insulin-dependent diabetes mellitus (NIDDM) and nondiabetic subjects both before and after ingestion of a carbohydrate meal isotopically with labeled [6 14C] glucose. In the postabsorptive state hepatic glucose appearance was higher ( P < .05) when determined with [2 3H] glucose than with [3 3H] glucose in the diabetic patients, but not in the nondiabetic subjects. After glucose ingestion the integrated responses of glucose appearance, systemic entry of ingested glucose, and hepatic glucose release all were higher ( P < .05) when determined with [2 3H] glucose compared to [3 3H] glucose in both the diabetic and nondiabetic subjects. However, the absolute differences between glucose turnover measured with [2 3H] and [3 3H] glucose were similar in the diabetic and nondiabetic subjects. Both isotopes provided a similar assessment of postprandial carbohydrate metabolism, indicating that either isotope can be used with equal efficacy to compare postprandial carbohydrate metabolism in patients with NIDDM and nondiabetic subjects.

The influence of body weight, age and glucose tolerance on the relationship between GIP secretion and beta-cell function in man.

The aim of the present study was to examine the association between insulin and gastric inhibitory polypetide (GIP) secretion in conditions characterized by insulin resistance, i.e. obesity, impaired glucose tolerance (IGT), non-insulin dependent diabetes mellitus (NIDDM) and aging. Obesity, IGT and aging were associated with an increased insulin/C-peptide response to a test meal. The GIP response to the test meal was 'blunted' in the obese subjects but normal in older subjects and patients with IGT, thereby refuting the hypothesis that GIP is involved in the hyperinsulinaemia of these conditions. In contrast, lean NIDDM subjects showed both a reduced insulin/C-peptide repsonse and a decreased GIP response to the test meal indicating that dysfunction of GIP secretion could be involved in the impaired beta-cell function in NIDDM. The data, therefore, suggest that hypersecretion of GIP does not contribute to hyperinsulinaemia and hyper-C-peptidaemia in insulin-resistant states. In contrast, hyposecretion of GIP may be involved in hypoinsulinaemia/hypo-C-peptidaemia observed in NIDDM.

Cellular mechanisms of insulin resistance in non-insulin-dependent (type II) diabetes

Recent studies have led to an enhanced understanding of cellular alterations that may play an important role in the pathophysiology of non-insulin-dependent diabetes mellitus (NIDDM). The insulin receptor links insulin binding at the cell surface to intracellular activation of insulin's effects. This transducer function involves the tyrosine kinase property of the beta-subunit of the receptor. It was found that adipocytes from subjects with NIDDM had a 50 to 80 percent reduction in insulin-stimulated receptor kinase activity compared with their non-diabetic counterparts. This defect was relatively specific for the diabetic state since no decrease was observed in insulin-resistant non-diabetic obese subjects. The reduction in kinase activity was accounted for by changes in the ratio of two pools of receptors, both of which bind insulin but only one of which is capable of tyrosine autophosphorylation and subsequent kinase activation; 43 percent of the receptors from non-diabetic subjects were capable of autophosphorylation compared with only 14 percent in the NIDDM group. A major component of cellular insulin resistance in NIDDM involves the glucose transport system. Exposure of cells to insulin normally results in enhanced glucose transport mediated by translocation of glucose transporters from a low-density microsomal intracellular pool to the plasma membrane. It was found that cells from NIDDM subjects had a marked depletion of glucose transporters in both plasma membranes and low-density microsomes, relative to obese non-diabetic control participants. Obese non-diabetic persons had a normal number of plasma membrane transporters but a reduced number of low-density microsome transporters in the basal state compared with lean control volunteers; insulin induced the translocation of relatively fewer transporters from the low-density microsome to the plasma membrane in the obese subgroups. In addition to the diminished number of glucose transporters, cells from both NIDDM and obese subjects had impaired functional activity of glucose carriers since decreased whole-cell glucose transport rates could not be entirely explained by the magnitude of the decrement in the number of plasma membrane transporters. Thus, impaired glucose transport is due to both a numerical and functional defect in glucose transporters. The cellular content of high-density microsomal transporters was the same in lean and obese control volunteers and NIDDM subjects, suggesting that transporter synthesis is normal and that cellular depletion results from increased protein turnover once transporters leave the high-density microsomal subfraction. Thus, the defects in NIDDM can be dissociated from those in non-diabetic obesity. In NIDDM, alterations exist at the level of the receptor kinase and the glucose transporter; in obesity, the defects include alterations in glucose transport but not in the receptor kinase.

Effects of Cottonseed Dietary Fiber on Metabolic Parameters in Diabetic Rats and Non-Insulin-Dependent Diabetic Humans

The objective of this study was to evaluate the effect of gland cottonseed dietary fiber (CSDF) containing 86% dietary fiber (mainly cellulose) on serum glucose levels in diabetic rats and in non-insulin-dependent diabetes mellitus (NIDDM) patients. A diet containing 15% CSDF given to streptozotocin-induced diabetic rats for 30 d tended to reduce the postprandial plasma glucose level curve. Alternatively, CSDF significantly increased fecal weight (15 +/- 3 vs. 5 +/- 2 g; P less than 0.01) and shortened transit time (20 +/- 2.24 vs. 11.2 +/- 0.8 h). CSDF had no effect on body weight and serum lipid levels. Twelve NIDDM subjects were given a meal tolerance test (MTT) with or without CSDF before and after daily supplementation of CSDF (16.5 g) in pita twice a day for a month. Incremental glucose levels were significantly (P less than 0.05) lower at 30, 60 and 180 min after the MTT containing CSDF than in subjects consuming a meal without CSDF. The insulin levels also tended to be lower. The NIDDM subjects tolerated the CSDF well. No flatulence or other side effects were exhibited. Plasma lipid levels remained unchanged. We therefore concluded that CSDF may have a potential benefit in the management of NIDDM.

Physiological importance of deficiency in early prandial insulin secretion in non-insulin-dependent diabetes.

Patients with non-insulin-dependent diabetes mellitus (NIDDM) have a deficiency in early prandial insulin secretion. To determine the contribution of this early deficiency to prandial hyperglycemia, exogenous intravenous insulin (1.8 U over 30 min) was delivered to eight NIDDM subjects in a profile designed to simulate the normal initial rise in insulin levels. The same dose of insulin was also administered 1) in the same profile but delayed by 30 min and 2) as a constant infusion over 180 min. Augmentation of the early insulin response caused a 33 +/- 4% reduction in the glycemic response to a mixed meal (P less than .005); the peak blood glucose increment above baseline was reduced by 1.4 mM (P less than .005) to an increment identical to nondiabetic subjects (3.3 +/- 0.3 vs. 3.2 +/- 0.2 mM), and blood glucose levels were still 0.9 mM lower after 180 min (P less than .05). In contrast, the delayed profile or constant infusion did not significantly alter the glycemic response to the meal. Early insulin augmentation resulted in elevated peripheral insulin levels initially (peak level 81 +/- 11 mU/L), but subsequent insulin and C-peptide levels were lower than in the control study (at 180 min after the meal, 22 +/- 5 vs. 33 +/- 8 mU/L, P less than .05, and 4.0 +/- 0.5 vs. 5.3 +/- 0.6 micrograms/L, P less than .02, respectively). Early insulin delivery caused free-fatty acid (FFA) levels to fall at a faster rate after the meal and also attenuated the initial rise in glucagon levels typical of NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Day-long integrated serum insulin and C-peptide profiles in patients with NIDDM. Correlation with urinary C-peptide excretion.

To determine whether non-insulin-dependent diabetes mellitus (NIDDM) is characterized by day-long hypoinsulinemia, we measured 24-h serum profiles for glucose, insulin, and C-peptide by use of a constant-rate blood-withdrawal technique in diabetic and control subjects fed isocaloric meals. When only lean subjects were considered, diabetic subjects (relative body weight 0.99 +/- 0.3) and control subjects (relative body weight 0.95 +/- 0.03) had similar 24-h integrated serum insulin concentrations (13.4 +/- 2.5 vs. 16.1 +/- 2.0 microU/ml, P NS) due to the offsetting effects of increased basal levels and decreased postprandial responses in NIDDM. In contrast, both basal and meal-stimulated insulin levels were decreased in obese NIDDM subjects (relative body weight 1.39 +/- 0.07) compared with obese control subjects (relative body weight 1.60 +/- 0.08), resulting in a 61% reduction in the 24-h integrated insulin value (18.7 +/- 1.5 vs. 48.4 +/- 13.7 microU/ml). Thus, the capacity to increase 24-h integrated serum insulin as a function of relative body weight was impaired in NIDDM subjects (r = 0.27, P NS) compared with control subjects (r = .70, P less than .01). In contrast, 24-h integrated C-peptide was decreased (P less than .01) in both lean (0.92 +/- 0.13 pM/ml) and obese (1.52 +/- 0.19 pM/ml) NIDDM patients compared with the respective control groups (1.50 +/- 0.13 and 3.03 +/- 0.44 pM/ml). The molar ratio of 24-h integrated C-peptide to insulin was diminished in lean but not obese NIDDM compared with control subjects. A 3-wk period of intensive insulin therapy led to normalization of the mean 24-h integrated insulin (but not integrated serum C-peptide) value in NIDDM compared with a control group that had an identical mean relative body weight. The 24-h urinary C-peptide measured on the same day as the serum profile was correlated (P less than .01) with both the 24-h integrated serum insulin (r = .69) and C-peptide (r = .67) concentrations in control subjects but not in NIDDM subjects (r = .20 and .04, respectively, P NS). Additionally, the urinary clearance of C-peptide was increased in NIDDM (38.1 +/- 7.8 vs. 20.4 +/- 1.7 ml/min in control subjects, P less than .05) and varied with treatment status (26.0 +/- 4.6 ml/min after insulin therapy).(ABSTRACT TRUNCATED AT 400 WORDS)

Decreased activation of skeletal muscle glycogen synthase by mixed-meal ingestion in NIDDM.

Glycogen synthase (GS) catalyzes the formation of glycogen in human skeletal muscle, the tissue responsible for disposal of a significant portion of an oral carbohydrate load. Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by fasting and postprandial hyperglycemia in conjunction with reduced rates of insulin-stimulated glucose disposal and storage in peripheral tissues, including muscle. Our objectives in this study were to determine whether ingestion of a mixed meal activates GS in control nondiabetic subjects and whether meal-related GS activation is reduced in NIDDM. To accomplish this, mixed formula meals were administered to 11 NIDDM and 9 age- and weight-matched nondiabetic control subjects. Plasma glucose and insulin values were measured before and for 90 min after meal ingestion. Skeletal muscle biopsies were performed just before and 90 min after meal ingestion for measurement of GS activity. Compared with control subjects, NIDDM subjects had significantly higher postprandial hyperglycemia and reduced postprandial hyperinsulinemia. GS was activated by meal ingestion in control subjects to a significantly greater extent than in NIDDM subjects. In NIDDM subjects, activation of GS was inversely correlated with fasting plasma glucose (r = .69, P less than .05). Therefore, NIDDM is characterized by reduced activation of a key step in the process of muscle glycogen repletion after a meal. Reduced activation of GS by a mixed meal in NIDDM may contribute to the reduced glucose disposal after a meal, thus contributing to the hyperglycemia observed in these subjects.