Normal insulin sensitivity of the islets of Langerhans in obese subjects with resistance to its glucoregulatory actions.

The ability of varying levels of circulating insulin to suppress alpha- and beta-cell secretion was assessed by plasma glucagon and C-peptide measurement in 6 obese and 6 nonobese subjects maintained in a euglycemic state, with an insulin concentration elevated by 10, 20, or 100 microU/ml above basal levels by a primed-continuous infusion of insulin. The 10-microU/ml increase did not suppress C-peptide levels significantly in either group. However, incremental increases in plasma insulin of approximately 20 and 100 microU/ml above basal suppressed plasma C-peptide by 0.27 +/- 0.14 and 0.53 +/- 0.07 pmol/ml, respectively, in the obese subjects (14% and 31% of the basal values of 2.20 +/- 0.18 and 2.19 +/- 0.26 pmol/ml, respectively) and by 0.16 +/- 0.06 and 0.17 +/- 0.06 pmol/ml in the nonobese subjects (20% and 25% the basal values of 0.74 +/- 0.11 and 0.78 +/- 0.11 pmol/ml, respectively). Plasma glucagon levels were suppressed to a similar degree in each group in a dose-related manner during both the 20-microU/ml and 100-microU/ml clamps. We were unable to identify an increment of insulin that suppressed C-peptide and/or glucagon in one group but not in another. These data demonstrate inhibition of alpha- and beta-cell secretion by insulin within its physiologic range in both non-obese and obese man, and exclude insulin resistance of alpha- and beta-cells in obese individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

A simplified method using somatostatin to assess in vivo insulin resistance over a range of obesity.

Twenty-one nondiabetic subjects, their weights ranging from 56 to 165 kg, received an infusion of glucose (420 mg/min), insulin (0.77 mU/kg/min), and somatostatin (500 microgram/h) for 150 min. A steady state level of plasma insulin and glucose was attained after 90 min. Endogenous insulin secretion determined by C-peptide measurement, and glucagon secretion remained suppressed throughout the period. With similar steady state levels of plasma insulin (SSPI) maintained in all subjects, the height of the steady state plasma glucose concentration (SSPG) was considered an index of total body sensitivity to insulin-mediated glucose uptake. A positive correlation between SSPG and the degree of obesity, as determined by the body mass index (BMI), was demonstrated (r = 0.70, P less than 0.001). No correlation was found between SSPI and BMI. The fasting plasma insulin concentration correlated with BMI (r = 0.82, P less than 0.0001) and SSPG (r = 0.80, P less than 0.0001). This method provides a simple safe measure of total body insulin resistance over a wide range of obesity and is independent of endogenous insulin secretion.

Insulin therapy in obese, non-insulin-dependent diabetes induces improvements in insulin action and secretion that are maintained for two weeks after insulin withdrawal.

The effects of rigorous insulin treatment on insulin action (insulin clamp) and secretion (plasma insulin response to glucose) were studied in 13 obese patients with non-insulin-dependent diabetes mellitus (NIDDM). Improvements were documented in fasting (P less than 0.0001) and postprandial (P less than 0.0001) plasma glucose concentrations, insulin secretion after oral glucose (P less than 0.001), and insulin action (P less than 0.005) after 30 days of therapy. Mean integrated plasma insulin response to glucose increased 2.5-fold after insulin therapy, but this improvement varied considerably from patient to patient. Insulin action also increased with insulin treatment and the resulting values were no longer significantly different from a weight- and age-matched group of subjects with normal glucose tolerance. However, there was considerable patient-to-patient variation in the degree to which insulin action was enhanced. The insulin-induced improvements in glucose tolerance persisted for at least 2 wk after insulin withdrawal, and were associated with continued increased insulin secretion and insulin action. In conclusion, control of hyperglycemia for 1 mo led to improvements in both insulin secretion and action in a series of obese patients with NIDDM that persisted for at least 2 wk after cessation of therapy.

Improvement of glucose homeostasis after exercise training in non-insulin-dependent diabetes.

Six obese patients with recent-onset, non-insulin-dependent diabetes underwent assessment of glucose tolerance, insulin secretory capacity, and insulin-induced glucose disposal before and after 6-10 wk of intensive aerobic training while maintaining body weight. Fasting plasma glucose declined in every subject (average = -33 mg/dl), and oral glucose tolerance (3 h integrated plasma glucose) improved in five of the six (average = -74 mg X 3 h/dl) after training. Individual improvement in control of plasma glucose was directly proportional to degree of hyperglycemia before training and correlated well with an observed improvement in the early (30-min) plasma insulin response to oral glucose (all six subjects). The response of insulin action to training was highly variable; although the observed increase in average insulin-induced glucose disposal rate (M) during the euglycemic clamp did not reach statistical significance in our small cohort, the relative change in M was directly related to reduction in fasting insulin levels after training. Our results show that regular endurance exercise is effective in improving glucose homeostasis and may serve as an adjunct to other modes of treatment in recent-onset, non-insulin-dependent diabetic individuals.

Altered insulin binding to monocytes and diploid fibroblasts from obese donors.

Insulin binding was studied in fibroblasts and monocytes from nondiabetic subjects with a range of body mass indices (BMI). Binding was compared in fibroblasts from extremely obese subjects and normal weight subjects. The [125I] insulin displacement curve for the obese subjects was shifted to the right. Scatchard analysis suggested that cells from the obese group have an increased number of receptors with decreased affinity. Significant correlations were observed between the cell donor's BMI and the concentration of insulin required to inhibit half of the [125I]insulin specifically bound to fibroblasts (r = 0.8; P less than 0.005), the high affinity dissociation constant (r = 0.8; P less than 0.005), and the number of receptors (r = 0.6; P less than 0.05). Insulin binding to monocytes was measured for nondiabetic Pima Indian subjects with a range of BMI values. Scatchard analysis of the data indicated that the high affinity dissociation constant was positively correlated with BMI (r = 0.6; P less than 0.02). The number of receptors was also positively correlated with BMI (r = 0.6; P less than 0.05). The observation that both cultured cells and monocytes exhibit changes in insulin binding that correlate with the obesity of the cell source suggests that the insulin resistance of obesity may be partially a reflection of genetic differences at the site of the insulin receptor.

Diminished effect of caloric restriction on control of hyperglycemia with increasing known duration of type II diabetes mellitus.

The effect of weight loss and caloric restriction on plasma glucose concentrations and insulin and glucagon secretion in response to oral and iv glucose and arginine infusions was examined in 8 subjects with type II diabetes mellitus of greater than 5 yr duration (long term diabetes). The findings of this study were compared to previous results in 10 subjects with similar degrees of obesity and fasting hyperglycemia but diabetes of less than 2 yr duration (recent-onset diabetes; fasting plasma glucose, 267 +/- 16.5 mg/dl in long term diabetics and 259 +/- 8.0 mg/dl in recent onset diabetics) and to a control group of 8 similarly obese but nondiabetic subjects. Both diabetic groups had impaired insulin responses on initial and final tests compared to control subjects. Response to dietary therapy was significantly poorer in the diabetics of longer duration (final fasting plasma glucose, 175 +/- 18.9 mg/dl in long term vs. 119 +/- 6.2 mg/dl in recent-onset subjects; P less than 0.01) despite a similar degree of weight loss and duration of diet therapy in the 2 groups. This difference in glucose tolerance occurred despite similar final insulin and glucagon responses in the diabetic groups. Subjects with type II diabetes of long duration appear to have a relatively greater degree of insulin resistance than subjects with more recent onset of the disease.

Reduced Na+, K+ -ATPase activity in intact red cells and isolated membranes from obese man.

Na+, K+ -ATPase activity was measured in red blood cells from 20 nondiabetic euthyroid male Pima Indians with varying degrees of obesity; their body mass indices ranged from 22-60 kg/m2. The na+, K+ -ATPase, measured both by 86Rb uptake in intact cells and ATP hydrolysis by purified membranes, was inversely correlated with body mass index (r = -0.62; P less than 0.005 and r = -0.75; P less than 0.0001, respectively). These results confirm that obesity is associated with decreased Na+, K+ -ATPase in intact red blood cells, and provide the first demonstration of a reduced sodium pump in isolated red cell membrane preparations from obese men.

The antilipolytic action of insulin in obese subjects with resistance to its glucoregulatory action.

To compare the ability of insulin to regulate lipolysis in lean and obese subjects, free fatty acid (FFA) suppression was compared in groups of six lean [body mass index, 25.7 +/- 1.1 (+/-SEM) kg/m2] and six obese (body mass index, 48.8 +/- 3.1) Pima Indians during euglycemic hyperinsulinemic clamps which increased plasma insulin levels approximately 10, 20, and 100 microU/ml above basal concentrations. Basal FFA concentrations were slightly, but not significantly, elevated in the obese group (445 +/- 35 vs. 406 +/- 40 mu eg/liter). The mean decline in FFA from basal after 60-90 min of insulin infusion in the obese group was somewhat less than that in the lean group at the lower doses [67 +/- 23 vs. 132 +/- 32 (P = NS) during the 10-microU clamp, and 144 +/- 39 vs. 217 +/- 20 (P = NS) during the 20-microU clamp] and was almost identical in the two groups during the 100-microU clamp (226 +/- 29 vs. 229 +/- 51). In contrast, insulin-mediated glucose disposal at all insulin increments was much lower in the obese group (0.33 +/- 0.03, 0.56 +/- 0.04, and 1.39 +/- 0.04 mg/kg X min) than in the lean group (0.78 +/- 0.06, 1.67 +/- 0.12, and 4.96 +/- 0.26; P less than 0.001). The data suggest that although the obese subjects exhibited significant resistance to the glucoregulatory action of insulin, there were only small changes in insulin's antilipolytic effects. Relative maintenance of sensitivity to the antilipolytic action of insulin in the presence of resistance to insulin's glucoregulatory action could maintain fat deposition in obese individuals.

Improvement of insulin secretion but not insulin resistance after short term control of plasma glucose in obese type II diabetics.

Insulin secretion and insulin resistance were examined in seven obese type II diabetics before and after control of plasma glucose levels without weight loss. Control was achieved by regular insulin injection (60-205 U/day in four doses). After 10 days of therapy, plasma insulin and C-peptide responses to oral glucose were significantly improved. Insulin-induced glucose rates, estimated by the glucose clamp technique, averaged 1.08 +/- 0.30 mg/kg. min (mean +/- SEM; n = 7) before treatment and were unchanged (1.08 +/- 0.25) after treatment. These indicate that short term control of plasma glucose improved insulin secretion but not insulin sensitivity. The impaired insulin secretion and insulin sensitivity in type II diabetics appears to be, in part, secondary to metabolic abnormalities associated with hyperglycemia.

Increased insulin resistance in obese, glucose-intolerant Southwestern American Indians: evidence for a defect not explained by obesity.

Increased in vivo resistance to insulin-mediated glucose disposal has been observed in obese subjects with normal glucose tolerance and in nonobese subjects with glucose intolerance. To determine whether the insulin resistance of glucose-intolerant obese subjects can be accounted for by obesity alone, insulin-mediated glucose disposal was measured in 14 glucose-intolerant and 21 nondiabetic. Southwestern American Indians with similar degrees of obesity. A mixture of insulin, glucose, and somatostatin was infused which delivered the same quantity of glucose and achieved similar plasma insulin concentrations in all subjects. Despite similar steady state plasma insulin levels, the mean steady state plasma glucose concentration was higher in the glucose-intolerant subjects than in weight-matched subjects with normal glucose tolerance (226 +/- 10 vs. 136 +/- 13 mg/dl; P < 0.0001). This increased resistance to insulin action was found in the presence of similar insulin binding to mononuclear cells (measured in 8 glucose-intolerant subjects and 9 subjects with normal glucose tolerance). In obese Southwestern American Indians with glucose intolerance, abnormalities beyond the site of insulin binding to its receptor may explain the observed increase in in vivo insulin resistance.

Hypergastrinemia in obese noninsulin-dependent diabetes: a possible reflection of high prevalence of vagal dysfunction.

To elucidate the relation of noninsulin-dependent (type II) diabetes mellitus to plasma levels of gastrin, pepsinogen I, and pepsinogen II, gastric acid secretion, and gastric emptying, we studied diabetic and nondiabetic obese Pima Indian subjects. Fasting and postprandial plasma gastrin concentrations were significantly higher (P less than 0.02) in diabetic than in nondiabetic subjects, but gastric acid outputs basally, after an acaloric liquid meal, and in response to betazole were similar in the two groups. Plasma pepsinogen I and pepsinogen II levels were also similar in both groups. A significant negative relation (r = -0.84; P less than 0.01) was found between basal gastrin levels and gastric acid production in nondiabetic Indians, but not in diabetic Pimas. The fractional gastric emptying rate of an acaloric liquid meal was significantly decreased in diabetic Pimas (P less than 0.01); and at least one test showing abnormal vagal function, as estimated by the Valsalva maneuver, heart rate changes between deep expiration and inspiration, and postural hypotension, was found in every diabetic subject. These findings suggest that hypergastrinemia in type II diabetes is not related to hypochlorhydria, but, instead, results from autonomic dysfunction with slow gastric emptying.

Changes in plasma lipoproteins accompanying diet therapy in obese diabetics.

Plasma lipoprotein cholesterol and triglyceride levels were measured in 24 obese not-insulin dependent Pima Indian diabetics and 9 obese nondiabetic controls before and after 1-8 months on a 500 calorie diet. The diabetics were divided into 3 groups--severe, recent onset (n = 10), severe long-term (n = 6), and borderline (n = 8). The diet regimen resulted in weight loss and improved glucose tolerance in all of the diabetics, and insulin secretion increased in the 2 groups of severe diabetics. After the period of weight loss, total plasma cholesterol had declined greater than 20%, and LDL cholesterol decreased 25% in all diabetic groups and in the controls. In all diabetic groups, HDL cholesterol did not decline; therefore the ratio of HDL/LDL cholesterol after diet therapy was significantly increased. In the controls HDL cholesterol declined with weight loss, and the distribution of HDL/LDL cholesterol remained constant. Plasma and VLDL triglyceride levels decreased in all groups in those with initial triglyceride levels greater than 150 mg/dl. The results indicate that weight loss in not-insulin dependent diabetics not only improves glucose tolerance, but also lowerss plasma lipids and reverses the dyslipoproteinemia often associated with this disorder. This may influence the risk of arteriosclerotic heart disease in these individuals.

Pancreatic polypeptide in Pima Indians: the influence of obesity and diabetes.

The influence of obesity and diabetes on circulating pancreatic polypeptide (PP) levels was studied in 62 Pima Indians and 22 caucasians. Plasma PP was determined in the fasting state and after a standardized test meal. Fasting and the postprandial PP responses were not significantly different among the Pima Indians whether nonobese, obese, or diabetic. However, their concentrations were significantly higher both fasting and postprandially compared to those of caucasians. In both groups the postprandial PP response was positively correlated with the fasting level. Fasting and postprandial PP levels positively correlated with age in Pimas.

Hyperinsulinemia in obesity: lack of relation to gastric emptying of glucose solution or to plasma somatostatin levels.

To investigate some factors that may be related to the hyperinsulinemia of obesity, we measured fractional gastric emptying rates and changes of circulating levels of glucose, insulin, and somatostatin-like immunoreactivity (SLI) following the intragastric instillation of glucose in age-matched obese and nonobese Pima Indians with normal glucose tolerance. Results for the nonobese Pimas were also compared with findings for age- and weight-matched Caucasians with normal glucose tolerance. The levels of fasting plasma insulin and the integrated insulin response to glucose were significantly greater (P less than 0.01) in obese than in nonobese Pimas. Mean rates of fractional gastric emptying, both in the basal state and after the glucose load, were similar for the three groups. The fractional gastric emptying rates after a glucose load were strongly correlated with the integrated responses of both plasma glucose and insulin in the nonobese Caucasians (r = 0.88, 0.90; P less than 0.01) but not in either Pima group. There were no significant differences in peripheral plasma SLI for any of the three groups, either in the basal state or after the glucose load. These findings suggest that the hyperinsulinemia of established obesity is not mediated by alterations in the gastric emptying rate of liquids or by peripheral plasma SLI concentrations. They do not, however, exclude defects in gastric emptying of solid foods. Nor do they exclude the possibility that gastric or D-cell abnormalities exist during the period of fat accumulation but recede after obesity is established.

Haemorrhage into the anterior pituitary during pregnancy after induction of ovulation with clomiphene.

A 34-year-old woman with secondary amenorrhoea and primary infertility became pregnant after treatment with clomiphene. She developed pre-eclampsia. Visual symptoms were experienced due to rapid enlargement of the anterior pituitary gland. The patient was delivered by Caesarean section. At subsequent craniotomy the patient was found to have haemorrhage into the pituitary gland, but histological examination of the pituitary tissue which was removed revealed no tumour tissue. One year after delivery the patient was still amenorrhoeic and had galactorrhoea with hyperprolactinaemia indicating that she probably had a small pituitary adenoma which was incompletely removed during neurosurgery.