James C. Beard

Quantification of the Relationship Between Insulin Sensitivity and β-Cell Function in Human Subjects: Evidence for a Hyperbolic Function

To determine the relationship between insulin sensitivity and β-cell function, we quantified the insulin sensitivity index using the minimal model in 93 relatively young, apparently healthy human subjects of varying degrees of obesity (55 male, 38 female; 18–44 yr of age; body mass index 19.5–52.2 kg/m2) and with fasting glucose levels <6.4 mM. SI was compared with measures of body adiposity and β-cell function. Although lean individuals showed a wide range of SI, body mass index and SI were related in a curvilinear manner (P < 0.0001) so that on average, an increase in body mass index was associated generally with a lower value for SI. The relationship between the SI and the β-cell measures was more clearly curvilinear and reciprocal for fasting insulin (P < 0.0001), first-phase insulin response (AIRglucose; P < 0.0001), glucose potentiation slope (n = 56; P < 0.005), and β-cell secretory capacity (AIRmax; n = 43; P < 0.0001). The curvilinear relationship between SI and the β-cell measures could not be distinguished from a hyperbola, i.e., SI × β-cell function = constant. This hyperbolic relationship described the data significantly better than a linear function (P < 0.05). The nature of this relationship is consistent with a regulated feedback loop control system such that for any difference in SI, a proportionate reciprocal difference occurs in insulin levels and responses in subjects with similar carbohydrate tolerance. We conclude that in human subjects with normal glucose tolerance and varying degrees of obesity, β-cell function varies quantitatively with differences in insulin sensitivity. Because the function governing this relationship is a hyperbola, when insulin sensitivity is high, large changes in insulin sensitivity produce relatively small changes in insulin levels and responses, whereas when insulin sensitivity is low, small changes in insulin sensitivity produce relatively large changes in insulin levels and responses. Percentile plots based on knowledge of this interaction are presented for evaluating β-cell function in populations and over time.

The effect of intensive endurance exercise training on body fat distribution in young and older men

Little is known about the effects of exercise interventions on the distribution of central and/or intra-abdominal (IA) fat, and until now there were no studies in the elderly. Therefore, in this study we investigated the effects of an intensive 6-month endurance training program on overall body composition (hydrostatic weighing), fat distribution (body circumferences), and specific fat depots (computed tomography [CT]), in healthy young (n = 13; age, 28.2 +/- 2.4 years) and older (n = 15; age, 67.5 +/- 5.8 years) men. At baseline, overall body composition was similar in the two groups, except for a 9% smaller fat free mass in the older men (P less than .05). The thigh and arm circumferences were smaller (P = .001 and P less than .05, respectively), while the waist to hip ratio (WHR) was slightly greater in the older men (0.92 +/- 0.04 v 0.97 +/- 0.04, P less than .01). Compared with the relatively small baseline differences in body composition and circumferences, CT showed the older men to have a twofold greater IA fat depot (P less than .001), 48% less thigh subcutaneous (SC) fat (P less than .01), and 21% less thigh muscle mass (P less than .001). Following endurance (jog/bike) training, both the young (+18%, P less than .001) and the older men (+22%, P less than .001) significantly increased their maximal aerobic power (VO2max). This was associated with small but significant decrements in weight, percent body fat, and fat mass (all P less than .001) only in the older men.(ABSTRACT TRUNCATED AT 250 WORDS)

The Insulin Sensitivity Index in Nondiabetic Man: Correlation Between Clamp-derived and IVGTT-derived Values

Although the minimal-model-based insulin sensitivity index (S1) can be estimated from the results of a simple 180-min intravenous glucose tolerance test (IVGTT), its relationship to widely accepted but technically more difficult clamp-based techniques has not been resolved in humans. Therefore we measured S1 by standard IVGTT, modified IVGTT, and clamp methods in 10 nondiabetic men with %IBW of 109 ± 12 (mean ± SD). In the euglycemic clamp studies, insulin was infused to bring insulin levels (IRI) from basal, 8 ± 4 μU/ml, to plateaus of 21 ± 5 and 35 ± 6 μU/ml. S1[clamp], measured as the increase in glucose (G) clearance per increase in IRI [δINF/(δIRI × G)], averaged 0.29 ± 0.09 ml/kg·min per μU/ml. In the IVGTT studies, 300 mg/kg G was given as an i.v. bolus, and G and IRI were measured for 180 min; in the modified (mod) IVGTT, tolbutamide (300–500 mg) was given i.v. 20 min after the G to observe the effect of an IRI peak on G removal after G level was free of initial “mixing” effects. The S1 estimated by computer did not differ significantly between standard [(6.9 ± 3.4) × 1O−4 min−1 per μU/ml] and modified [(6.7 ± 3.5) × 10−4 min−1 per μU/ml] tests, indicating no bias due to the differing insulin patterns and levels. There was a strong positive correlation between S1 (mod IVGTT) and S1(clamp): r = 0.84; N = 10; P < 0.002. The correlation between S1(standard IVGTT) and S1(clamp) was 0.54, suggesting the modified test is less “noisy” Nonetheless, in eight euglycemic women with a wider range of adiposity, S1(standard IVGTT) has been significantly correlated with %IBW (r = −0.72) and basal IRI (r = −0.84). The correlation between S1 measures by clamp and IVGTT methods provides one step toward validation of the minimal model for studies of insulin action in man.

Effects of physical conditioning on fibrinolytic variables and fibrinogen in young and old healthy adults.

BackgroundThe effects of 6 months of intensive endurance exercise training on resting tissue-type plasminogen activator (t-PA) activity, plasminogen activator inhibitor type 1 (PAI-1) activity, t-PA antigen, and fibrinogen were studied in 10 young (24–30 years) and in 13 old male subjects (60–82 years). Methods and ResultsAfter training, maximum oxygen consumption was increased in the young group by 18% (44.9±5.0 to 52.9±6.6 ml/kg/min, p <0.001), whereas it was increased in the old group by 22% (29.0±4.2 to 35.5±3.6 ml/kg/min, p < 0.001). The young group had no significant changes in any of the measured variables, whereas the old group had a 39% increase in t-PA activity (0.82 + 0.47 to 1.14 + 0.42 IU/ml, p < 0.03), a 141% increase in the percentage of t-PA in the active form (11.1+7.7 to 26.8 + 15.1%, p < 0.01), a 58% decrease in PAI-1 activity (8.4 + 4.9 to 3.5±1.7 AU/mI, p < 0.01), and a 13% decrease in fibrinogen (3.57±0.79 to 3.11±0.52 gIl, p < 0.01). ConclusionsWe conclude that intensive exercise training enhances resting t-PA activity and reduces fibrinogen and PAI-1 activity in older men. These effects are potential mechanisms by which habitual physical activity might reduce the risk of cardiovascular disease.

Pathophysiology of insulin secretion in non-insulin-dependent diabetes mellitus

The pathogenesis of the abnormal metabolic state in patients with non-insulin-dependent diabetes (NIDDM) is controversial. Even the term NIDDM stirs controversy because of the easily drawn inference that individuals with this form of diabetes do not need insulin treatment. Yet many patients with NIDDM are treated with insulin; some even develop hyperosmolar coma if not given insulin. Ketoacidosis, however, is very infrequent in this syndrome, implying that these patients are not dependent on insulin treatment to prevent mass mobilization of fatty acids and ketone bodies. The phrase noninsulin-dependent is therefore appropriate when used in this restricted fashion but inappropriate when used to imply adequacy of insulin secretion. The evaluation of the adequacy of islet function in this syndrome has been complex, since there is no standard of insulin output that can be defined for normal islets without specifying the physiologic setting under which the assessment has been made. For example, individuals with normal glucose levels but variable degrees of obesity have widely varying insulin secretion rates. Thus, the choice of controls is critical when comparing islet function in NIDDM to normal. In addition, the efficiency of the B-cell response to a challenge (e.g., oral glucose tolerance test) can markedly influence the magnitude of the stimulatory glucose level during the period of testing. For example, a subject with some impairment of insulin output will tend to become more hyperglycemic during the test. The hyperglycemia may then stimulate more insulin secretion so that the overall insulin output may appear equal to or even greater than that of a normal individual. In such a closed-loop system, strict control of input variables is necessary to evaluate whether or not insulin secretion is normal. As will be discussed, control of glucose level and other variables is seldom accomplished in dynamic glucose tolerance tests. As will be presented in this review, the development of appropriately controlled studies of islet function has provided convincing evidence that islet B-cell function is abnormal in patients with NIDDM. Since these studies are based on an understanding of normal islet function, normal islet B-cell physiology is discussed before pathophysiology. Finally, the implications of this analysis for the treatment of NIDDM with diet, hypoglycemic sulfonylureas, and insulin will be discussed.

The Contribution of Insulin-Dependent and Insulin-Independent Glucose Uptake to Intravenous Glucose Tolerance in Healthy Human Subjects

Glucose disposal occurs by both insulin-independent and insulin-dependent mechanisms, the latter being determined by the interaction of insulin sensitivity and insulin secretion. To determine the role of insulin-independent and insulin-dependent factors in glucose tolerance, we performed intravenous glucose tolerance tests on 93 young healthy subjects (55 male, 38 female; 18–44 years of age; body mass index, 19.5–52.2 kg/m2). From these tests, we determined glucose tolerance as the glucose disappearance constant (Kg), calculated β-cell function as the incremental insulin response to glucose for 19 min after an intravenous glucose bolus (IIR0-19), and derived an insulin sensitivity index (SI) and glucose effectiveness at basal insulin (SG) using the minimal model of glucose kinetics. To eliminate the effect of basal insulin on SG and estimate insulin-independent glucose uptake, we calculated glucose effectiveness at zero insulin (GEZI = SG [SI × basal insulin]). Insulin-dependent glucose uptake was estimated as SI × IIR0-19, because the relationship between SI and β-cell function has been shown to be hyperbolic. Using linear regression to determine the influence of these factors on glucose tolerance, we found that GEZI was significantly related to Kg (r = 0.70; P < 0.0001), suggesting a major contribution of insulin-independent glucose uptake to glucose disappearance. As expected, SI × IIR0-19 also correlated well with Kg (r = 0.74; P < 0.0001), confirming the importance of insulin-dependent glucose uptake to glucose tolerance. Although IIR0-19 alone correlated with Kg (r = 0.35; P = 0.0005), SI did not (r = 0.18; P > 0.08). By multiple regression, 72% of the variance in Kg could be explained by GEZI and S1 × IIR0-19 (r = 0.85; P < 0.0001). We conclude that insulin-independent glucose uptake is a major determinant of intravenous glucose tolerance and that the interaction of insulin sensitivity and insulin levels are more important than either factor alone as a determinant of intravenous glucose tolerance.

Increased β-Cell Secretory Capacity as Mechanism for Islet Adaptation to Nicotinic Acid-Induced Insulin Resistance

To determine whether prolonged nicotinic acid (NA) administration produces insulin resistance and, if so, how the normal pancreatic islet adapts to prolonged insulin resistance, we administered incremental doses of NA to 11 normal men for 2 wk, ending at 2 g/day. Insulin sensitivity was measured with Bergmans minimal model. Islet function was evaluated by measurement of acute insulin (AIR) and glucagon (AGR) responses to arginine at three glucose levels. Insulin resistance was demonstrated and quantified by a marked drop in the insulin sensitivity index (S1) from 6.72 ± 0.77 to 2.47 ± 0.36 × 10−5 min−1/pM (P < .0001) and resulted in a doubling of basal immunoreactive insulin levels (from 75 ± 7 to 157 ± 21 pM, P < .001) with no change in fasting glucose (5.5 ± 0.1 vs. 5.7 ± 0.1 mM). Proinsulin levels also increased (from 9 ± 1 to 15 ± 2 pM, P < .005), but the ratio of proinsulin to immunoreactive insulin did not change (12.7 ± 1.9 vs. 10.3 ± 1.9%). β-Cell changes were characterized by increases in the AIR to glucose (from 548 ± 157 to 829 ± 157 pM, P < .005) and in the AIR to arginine at the fasting glucose level (from 431 ± 54 to 788 ± 164 pM, P < .05). At the maximal hyperglycemia level the AIR to arginine represents β-cell secretory capacity, and this increased with administration of NA (from 2062 ± 267 to 2630 ± 363 pM, P < .05). From the AIRs to arginine an estimate of the glucose level giving half-maximal AIR to arginine can be calculated. This measure did not increase (10.0 ± 0.5 vs. 9.6 ± 0.9 mM). The AGRs to argininewere reduced at all glucose levels during NA administration. Thus, the pancreatic islet adapts to the prolonged insulin resistance induced by NA. This adaptation comprises a combination of increased insulin secretion and reduced glucagon secretion. The changes in insulin secretion can be entirely explained by an increase in the secretory capacity of the β-cell.

Insulin Resistance and Impaired Insulin Secretion in Subjects with Histories of Gestational Diabetes Mellitus

NIDDM is characterized by decreased insulin secretory responses to glucose and to nonglucose stimuli, hyperglucagonemia, and decreased tissue sensitivity to insulin. However, it hasbeen unclear which of these abnormalities, if any, precedes the others. Since women with histories of gestational diabetes mellitus (GDM) are at high risk for eventual development of NIDDM, we measured B- and A-cell function and tissue sensitivity to insulin in eight normoglycemic, postpartum women with recent histories of GDM and in eight control subjects pair-matched for age and percent of ideal body weight. Fasting plasma glucose levels in subjects with former GDM tended to be slightly higher than in matched controls (98 ± 3 versus 92 ± 2 mg/dl, P = 0.07). Basal plasma insulin in subjects with former GDM was significantly higher than in controls (22 ± 4 versus 14 ± 2 μUml, P = 0.05). During an intravenous glucose tolerance test (IVGTT), relative first- and second-phase insulin responses to glucose were decreased in subjects with former GDM (2316 ± 560 versus 7798 ± 1036% of basal · min, P = 0.004; and 8340 ± 946 versus 14,509 ± 2556, P = 0.04). An index of sensitivity to insulin, S1, calculated from the IVGTT, was also lower in former GDM (1.23 ± 0.69 × 10 4 versus 3.58 ± 0.78 × 10−4 min−1μU/ml, P = 0.001). Acute insulin responses to 5 g i.v. arginine were measured at plasma glucose levels of approximately 95, 215, and 600 mg/dl. The response at 600 mg/dl is termed the AIRmax andis used asan index of glucoseregulated insulin secretory capacity. Insulin responses to arginine at all glucose levels were similar in both groups. However, AIRmax, which was inversely correlated with S1 in controls, appeared low for the degree of insulin resistance informer GDM. Glucagon responses to arginine obtained at normoglycemia and suppressibility of such responses by hyperglycemia (600 mg/dl) were similar in both groups. We conclude that women with histories of GDM, who are predisposed to NIDDM, have impairments both of insulin secretion and of insulin action before the development of overt hyperglycemia.

The Effect of Chronic Sulfonylurea Therapy on Hepatic Glucose Production in Non-insulin-dependent Diabetes

In 20 patients with untreated non-insulin-dependent diabetes mellitus (NIDDM), there was a positive relationship between fasting plasma glucose (FPG) and glucose production rate, calculated by the isotope dilution technique (r = 0.72, P < 0.001). This suggests that glucose production rate is an important determinant of FPG in untreated NIDDM. Fifteen patients were also studied during therapy with chlorpropamide for 3–6 mo. During therapy, FPG was lower (133 ± 9 vs. 216 ± 20 mg/dl, mean ± SEM; P < 0.001), glucose production was lower (59.5 ± 2.0 vs 77.6 ± 4.9 mg/m2/min; P < 0.005), and there was a significant correlation between the fall in glucose production and the fall in FPG (r = 0.59, P < 0.05). Fasting IRI levels increased in some, but not all, patients during chlorpropamide (untreated 18 ± 2, treated 21 ± 2 μU/ml; P = NS). However, there was a significant relationship between the percent rise in IRI and the fall in glucose production during treatment (r = 0.75, P < 0.001). Patients with a rise in fasting insulin during therapy had a greater fall in glucose production than those whose insulin did not rise (25.4 ± 8.1 vs. 7.8 ± 2.4 mg/m2/min; P < 0.005). When a low-dose insulin infusion was given to approximate the increases of portal venous insulin during therapy, similar falls of glucose production occurred. We conclude that inhibition of endogenous glucose production during chronic chlorpropamide therapy is an important mechanism for the lowering of FPG and that enhanced insulin secretion is the reason for the major part of this inhibition. The small fall in glucose production in those patients whose insulin level did not rise during therapy suggests an additional contribution by some other mechanism.

Reduction of Glycemic Potentiation: Sensitive Indicator of β-Cell Loss in Partially Pancreatectomized Dogs

To determine which test of islet function is the most sensitive indicator of subclinical β-cell loss, we studied six conscious dogs before and 1 and 6 wk after removal of the splenic and uncinate lobes [64 ± 2% pancreatectomy (PX)]. To assess hyperglycemic potentiation, acute insulin secretory responses (AIR) to 5 g i.v. arginine were measured at the fasting plasma glucose (FPG) level after PG was clamped at ∼250 mg/dl and after PG was clamped at a maximally potentiating level of 550–650 mg/dl. FPG levels were unaffected by PX (112 ± 4 mg/dl pre-PX vs. 115 ± 5 mg/dl 6 wk after PX, P NS). Similarly, basal insulin levels remained constant after PX (11 ± 2 μU/ml pre-PX vs. 11 ± 1 μU/ml 6 wk after PX, P NS). The AIR to 300 mg/kg i.v. glucose decreased slightly from 42 ± 9 μU/ml pre-PX to 32 ± 5 μU/ml 6 wk after PX (P NS), and thus the β-cell loss was underestimated. In contrast, insulin responses to arginine declined markedly after PX. The AIR to arginine obtained at FPG levels declined from 23 ± 3 μU/ml pre-PX to 13 ± 2 μU/ml 6 wk after PX (P = .04). The AIR to arginine obtained at PG levels of ∼250 mg/dl declined even more, from a pre-PX value of 56 ± 7 μU/ml to 21 ± 4 μU/ml 6 wk after PX (P = .02). However, the largest decline in AIR to arginine occurred at PG levels of 550–650 mg/dl (113 ± 13 μU/ml pre-PX vs. 28 ± 7 μU/ml 6 wk after PX, P = .001), thus indicating a marked decrease of maximal glycemic potentiation. Basal levels of glucose and insulin and AIRs to glucose and arginine obtained 1 wk after PX were similar to those obtained 6 wk after PX. The second purpose of the study was to explore mechanisms by which compensation of this β-cell loss occurs and by which hyperglycemia is avoided. One possibility is a reduction of glucagon secretion, but immunoreactive glucagon levels and glucagon secretory responses to arginine measured at three PG levels remained unchanged after PX. Similarly, tissue sensitivity to insulin, measured with euglycemic clamps at two elevated insulin levels, and insulin clearance remained unchanged after PX. Thus, the mechanism for maintenance of euglycemia after partial PX in the dog remains unclear. In summary, a reduction in glycemic potentiation of the insulin response to arginine was found to be the best means of detecting the subclinical β-cell loss induced by a two-thirds PX in dogs.