Insulin resistance in latent autoimmune diabetes of adulthood.

Insulin resistance in patients with latent autoimmune diabetes of adulthood (LADA) was determined by homeostasis model assessment (HOMA). LADA was identified by a clinical phenotype of type 2 diabetes with antibodies to GAD65 and/or IA-2/ICA512. All patients were managed with insulin therapy. Insulin resistance in LADA was lower than in antibody-negative type 2 diabetes, higher than in normal humans and in recent-onset type 1 diabetes, and similar to that in long-term type 1 diabetes. Mean values for HOMA varied linearly with mean values for BMI, which accounted for much of the insulin resistance in these forms of diabetes. LADA resembles long-term type 1 diabetes with respect to insulin resistance and BMI, but occurs at an older age.

Autoantibodies and HLA susceptibility markers in Canadian first-degree relatives of patients with type 1 diabetes.

We examined the frequencies of autoantibodies to glutamate decarboxylase, GAD65, protein tyrosine phosphatase, IA-2/ICA512, and insulin, and of HLA class II markers in ICA-positive first-degree relatives of patients with type 1 diabetes. Our results indicate that while the presence of HLA susceptibility markers is associated with anti-islet autoantibodies, protective DQB1 markers do not absolutely prevent development of autoantibodies or progression to autoimmune diabetes.

Glucose turnover and insulin sensitivity in rats with pancreatic islet transplants.

To study the metabolic effects of insulin derived from islet grafts, oral glucose tolerance (OGT) and glucose turnover were examined in streptozotocin-induced diabetic Lewis rats rendered normoglycemic by syngeneic islet grafts in the renal subcapsular space (REN), in REN with renal vein-to-mesenteric vein anastomosis (REN-RMA), in the liver (intrahepatic [IH]), or in a parahepatic omental pouch (POP) and compared with normal rats. Normal OGT was found at 1 month posttransplant in all animals receiving approximately 3,000 islets, with hyperinsulinemic responses in the REN group compared with the other groups, and with higher C-peptide responses in the IH group than in the other groups (P < 0.05 by one-way analysis of variance). Glucose turnover studies in the insulin-stimulated steady state (INS-SS; infusion of insulin at 10 pmol x kg(-1) x min(-1)) at 2 months posttransplant showed that whole body glucose disappearance rates (Rd) were similar in all groups, but the REN group had higher steady-state insulin levels than the other groups. Glucose infusion rates (GIRs) were lower in the REN and IH groups than in the other groups. Apparent endogenous glucose production (EGP) was not completely inhibited in the REN and IH groups, while complete inhibition was observed in the other groups. When INS-SS insulin levels were matched to the level in REN rats by increasing the insulin infusion rate to 20 pmol x kg(-1) x min(-1) in REN-RMA, IH, and normal rats, GIR and Rd were elevated, exceeding those values in REN rats, but GIR in IH rats was still lower than in REN-RMA and normal rats. Thus, 1) in the REN group, impairment of inhibition of EGP and of stimulation of Rd by exogenous insulin contribute to insulin resistance; 2) in the IH group, incomplete inhibition of EGP is the major determinant of insulin resistance; and 3) with portal delivery of insulin in the REN-RMA and POP groups, normal insulin sensitivity is preserved. The present study confirms that hepatic portal delivery of islet secretions is necessary for physiological regulation of glucose metabolism. The study also suggests the IH grafts do not provide physiological regulation of glucose metabolism, raising the question of whether the liver is an appropriate site for insulin-secreting tissue replacement therapy in diabetes.

Insulin resistance prevented by portal delivery of insulin in rats with renal subcapsular islet grafts.

We determined the metabolic effects of insulin derived from renal subcapsular islet grafts, either with systemic delivery of insulin through renal venous drainage (REN) or with portal delivery of insulin after renal vein-to-superior mesenteric vein anastomosis (RMA), in streptozotocin-induced diabetic Lewis rats, in comparison with normal rats. After gavage glucose, the plasma glucose responses were similar to normal in REN and RMA rats; however, hyperinsulinemia occurred in REN rats (area under the concentration curves [AUCs] of insulin, 27 +/- 3 nmol x 1(-l) min) in comparison with RMA (14 +/- 2) and normal rats (19 +/- 2), P < 0.003, with no difference in C-peptide responses. The ratio of AUC C-peptide to AUC insulin was lower in REN (2.0 +/- 0.2) than in RMA (3.4 +/- 0.3) and normal animals (3.2 +/- 0.3), P < 0.0005. In euglycemic-hyperinsulinemic clamp studies using the same insulin infusion rate (10 pmol x kg(-1) x min(-1), insulin resistance was found in REN animals (mean glucose infusion rate [GIR], REN: 7.5 +/- 1.2; RMA: 12.0 +/- 1.2; normal: 12.7 +/- 1.0 mg x kg(-1) x min(-1); P < 0.008), with higher steady-state insulin levels in REN (554 +/- 63 pmol/l) than in RMA (291 +/- 26) and normal rats (269 +/- 60), P < 0.0001. With matching steady-state insulin levels in RMA and REN rats during infusion of insulin at 20 pmol x kg(-1) x min(-1) in RMA rats (steady-state insulin 623 +/- 64 pmol/l), GIR was 15.7 +/- 0.7 mg x kg(-1) x min(-1). Thus, systemic delivery of insulin from islet grafts is associated with hyperinsulinemia, insulin resistance, and decreased metabolic clearance of insulin. These abnormalities are prevented by portal delivery of insulin from islet grafts in the same site. The findings are consistent with the hypothesis that portal delivery of insulin is important in maintenance of normal whole-body insulin sensitivity.

Dietary fish oil enhances insulin sensitivity in miniature pigs.

The effects of dietary fish oil, MaxEPA, and corn oil on insulin sensitivity were examined in male miniature pigs. The pigs (20-35 kg) received 750 g of nonpurified diet per day (160 g/kg protein, 50 g/kg fat) with the addition of either 30 g corn oil or 30 g MaxEPA, resulting in 90 g total fat per kg diet for 4-5 wk. The MaxEPA diet provided 12.6 g (n-3) polyunsaturated fatty acids per kg diet (6.7 g eicosapentaenoic acid, 4.8 g docosahexaenoic acid), 4.7 g (n-3) polyunsaturated fatty acids and 147 mg cholesterol. The corn oil diet provided 22.7 g (n-6) polyunsaturated fatty acids per kg diet and no (n-3) polyunsaturated fatty acids; cholesterol was added to equal the amount in the MaxEPA. After overnight withdrawal of food, intravenous glucose tolerance tests were conducted in conscious pigs by using previously placed jugular vein catheters. Plasma glucose responses and the areas under the plasma glucose curves were similar in seven MaxEPA- and five corn oil-fed pigs. However, the incremental areas under the insulin curves were significantly lower for the pigs fed MaxEPA. Thus values for insulin sensitivity (SI), determined with Bergman's minimal model, were significantly higher for MaxEPA than for corn oil-fed pigs, whereas the rate of glucose disappearance (KG), did not differ between the two groups. Therefore, substitution of (n-3) for (n-6) polyunsaturated fatty acids in dietary lipids is associated with enhanced insulin sensitivity in male pigs.

Continued insulin dependence despite normal range insulin sensitivity and insulin connecting peptide levels in a kidney/islet transplant patient.

OBJECTIVE: The majority of islet transplant recipients remain insulin-requiring, although many have near-normal connecting peptide (CP) levels. Insulin resistance may be one possible cause of the continuing need for exogenous insulin in islet transplant recipients. To assess this, we have studied the insulin sensitivity index (S1) in one patient with near-normal CP levels after islet transplant who remained insulin-requiring. RESEARCH DESIGN AND METHODS: The islet transplant recipient is a 36-year-old woman with no residual CP who received a kidney transplant, followed 7 days later by an islet transplant. The islets were infused into the liver via the umbilical vein. Induction immunosuppression consisted of OKT3, prednisone, cyclosporin A, and azathioprine, with maintenance on the latter three. RESULTS: Maximum CP levels after a standardized Sustacal meal were 2.09, 1.18, 0.85, and 0.81 nmol/l at 1,6,18, and 24 months posttransplant, respectively. Insulin requirements at the same times were 0.27, 0.45, 0.49, and 0.62 U.kg(-1).d(-1), while S1 was 36.3, 53.3, and 13.2 min (-1).nmol(-1).ml at 6,18, and 24 months, respectively. This compares with S1 values of 43.3+/- 10.0 min (-1).nmol(-1).ml for normal subjects. CONCLUSIONS: This patient had near-normal S1 and CP levels, but she was unable to discontinue insulin therapy, suggesting that other factors are critical. Despite this, she maintained normal or near-normal glycated hemoglobins, indicating metabolic benefit from the islet transplant.

Rats with portal-caval vein transposition show hyperinsulinemia and insulin resistance.

To compare the metabolic effects of portal and systemic delivery of insulin, we used portal-caval transposition (PCT) in rats to provide total systemic diversion of splanchnic venous blood. PCT rats exhibited normal weight gain, liver histology, liver-function tests, glycosylated hemoglobin, arterial blood pressure, and hepatic blood flow. Mean liver weight relative to body weight was 12% lower in PCT rats than in sham-operated control (CTR) rats 30 days following transposition. Indwelling venous catheters were established to facilitate metabolic studies in conscious, minimally restrained animals. Postabsorptive plasma glucose and C-peptide (CPEP) levels were similar in PCT and CTR rats; however, postabsorptive immunoreactive insulin (IRI) levels were elevated in PCT rats (67 +/- 3.1 v 49 +/- 3.5 pmol.L-1, P < .002, n = 11 v 11), as were postabsorptive plasma glucagon levels (570 +/- 67 v 240 +/- 11 ng.L-1, P < .001, n = 11 v 16) at similar body weights. The postabsorptive CPEP/IRI concentration ratio was lower in PCT than in CTR rats (4.0 +/- 0.3 v 6.0 +/- 0.6, P < .02), suggesting reduced hepatic extraction of insulin. Insulin sensitivity (IS), determined by minimal model analysis of frequently sampled intravenous glucose tolerance tests yielding the sensitivity index (SI), was reduced in PCT compared with CTR (61 +/- 5.6 v 86 +/- 9.0 (mumol.L-1)-1.min-1, P < .04, n = 9 v 10). During euglycemic-hyperinsulinemic clamps, glucose infusion rates (GIRs) from 60 to 120 minutes were lower in PCT than in CTR rats (6.0 +/- 0.3 v 8.0 +/- 0.4 g.kg-1.min-1, P < .002, n = 9 v 7) with matching plasma IRI levels, confirming the reduced IS in PCT rats. Areas under the concentration curves ([AUCs] 0 to 150 minutes) for glucose tolerance tests (gavage) indicated that plasma glucose excursion was similar in PCT and CTR rats whereas AUC IRI was significantly higher in PCT than in CTR rats (23 +/- 1.3 v 18 +/- 0.6 nmol.L-1.min, P < .009, n = 11 v 11). However, AUC CPEP for oral glucose tolerance tests was lower in PCT than in CTR rats (55 +/- 3.4 v 68 +/- 4.8 nmol.L-1.min, P < .05), indicating decreased insulin secretion. Thus, the mean ratio AUC CPEP/AUC IRI was significantly lower in PCT rats (2.5 +/- 0.2 v 3.8 +/- 0.3, P < .002), again suggesting reduced hepatic extraction of insulin. Thus, euglycemia after PCT was accompanied by elevated postabsorptive and glucose-stimulated levels of IRI in systemic blood, postabsorptive hyperglucagonemia, and decreased insulin secretion in response to glucose challenge (gavage), with diminished hepatic extraction of insulin and decreased IS. The PCT model illustrates the insulin-resistant adaptive state that results from systemic delivery of insulin, and indicates the importance of hepatic portal delivery of insulin and possibly of other gastroenteropancreatic hormones in the maintenance of IS and physiological metabolic control.

Glucagon-like peptide I reduces postprandial glycemic excursions in IDDM.

Effects of human glucagon-like peptide I (GLP-I)(7-36)amide were examined in volunteers having insulin-dependent diabetes mellitus (IDDM) with residual C-peptide (CP) secretion (n = 8, 7 men and 1 woman; age, 31 +/- 1.4 years; body mass index, 24.7 +/- 0.7 kg/m2; duration of diabetes, 3.2 +/- 0.8 years; insulin dose, 0.41 +/- 0.05 U.kg-1.day-1; meal-stimulated CP, 1.0 +/- 0.2 nmol/l [means +/- SE]). After a mixed meal (Sustacal, 30 kJ/kg body wt), intravenous injection of GLP-I, 1.2 pmol.kg-1.min-1 through 120 min, virtually abolished increments of plasma glucose, CP, pancreatic polypeptide (PP), and glucagon concentrations, with no significant effect on plasma gastrin levels during the infusions. At reduced dosage (0.75 pmol.kg-1.min-1), GLP-I had lesser effects on plasma glucose and CP levels. On cessation of intravenous GLP-I infusions after the meals, plasma glucose, CP, PP, and glucagon concentrations rebounded toward control levels by 180 min, and the response of plasma gastrin was prolonged. These rebound responses are consistent with intestinal delivery of food retained in the stomach on escape from inhibition of gastric emptying by GLP-I. Infusion of 1.2 pmol.kg-1.min-1 GLP-I with 20 g glucose (10% dextrose in water) injected intravenously over 60 min enhanced plasma responses of immunoreactive CP; the mean incremental areas under concentration curves (0-60 min) increased sixfold, but the glycemic excursion was not affected. Thus, in CP-positive IDDM, pharmacological doses of GLP-I reduce glycemic excursions after meals by a mechanism(s) not dependent on stimulation of insulin secretion, presumably involving delayed gastric emptying.(ABSTRACT TRUNCATED AT 250 WORDS)

Nicotinamide and diabetes prevention.

Individuals at high risk of developing insulin-dependent diabetes mellitus can now be identified by immunologic testing. This ability to predict future cases of IDDM raises the possibility of intervention to prevent the disease. An intervention study in New Zealand using nicotinamide treatment showed a 50% reduction in the development of IDDM in a 5-year period.

Parallel regulation of the local vascular and systemic metabolic effects of insulin.

Recent studies have focused on the link between the development of disordered vascular regulation (e.g. hypertension) and alteration in the effects of insulin to mediate glucose uptake. We and others have recently demonstrated that insulin is a potent vasodilator. Further, it has been suggested that impairment of insulin-mediated vasodilation may be an important contributing factor in the development of increased peripheral resistance. However, whether the local vascular effects of insulin correlate with its systemic glucose regulatory effects remains unclear. Therefore, we assessed both vascular sensitivity to insulin (using dorsal hand vein linear variable differential transformer techniques) and glucoregulatory sensitivity to insulin (using the minimal model technique applied to a frequently sampled iv glucose tolerance test) in 12 normotensive nondiabetic volunteers. In these subjects, metabolic sensitivity to insulin and venous sensitivity to insulin were highly correlated (r2 = 0.42; P = 0.02). Additionally, vascular sensitivity to insulin was inversely correlated with fasting C-peptide levels (r2 = 0.49; P = 0.02). Both systemic and vascular sensitivities to insulin were also highly correlated with body mass index. These studies demonstrate that the glucoregulatory effects of insulin are paralleled by its local vasodilating effects and continue to support this linkage as an important factor in the correlation between alterations in systemic sensitivity to insulin and the development of elevated peripheral resistance in hypertension and obesity.

Dietary fish oil does not alter glucose tolerance in conscious rats.

We examined the effect of dietary fish oil (MaxEPA) and sunflower seed oil on glucose tolerance in male Wistar rats. Semipurified diets containing 100 g oil/kg diet were administered for 30 d. The fish oil diet contained 26 g (n-3) fatty acids, 16 g eicosapentaenoic acid and 10.4 g docosahexaenoic acid/kg diet. Phospholipids from liver, pancreas, and pancreatic islets were enriched in eicosapentaenoic and docosahexaenoic acids by the fish oil diet. In unfed pentobarbital-anesthetized rats, both basal plasma insulin concentration and insulin responses to intravenous glucose were significantly lower for fish oil-fed rats although glucose responses were similar; however, incremental excursions in plasma insulin over the basal concentrations did not differ. Intravenous glucose tolerance was also examined in conscious unfed rats under minimal restraint. Responses of plasma glucose and insulin were similar for fish oil- and sunflower oil-fed groups. Furthermore, in another experiment, intravenous glucose tolerance tests were similar for conscious rats provided with either 100 g fish oil or corn oil/kg nonpurified diet. Thus, glucose-induced insulin secretion is lower in rats fed fish oil than in rats fed sunflower oil, when tests are conducted in pentobarbital-anesthetized animals but not when tests are performed in conscious rats; there was no effect on plasma glucose in either anesthetized or nonanesthetized rats. Therefore, substitution of (n-3) for (n-6) polyunsaturated fatty acids in tissue phospholipids does not alter plasma glucose or insulin in conscious male Wistar rats.

Hepatic extraction of insulin after stimulation of secretion with oral glucose or parenteral nutrients.

To determine whether hepatic extraction of insulin differs when glucose is administered by parenteral and physiological routes, we studied responses to oral glucose and to intravenous (IV) infusion of glucose or glucose plus arginine in normal volunteers. As in earlier studies, when IV glucose infusions were empirically programmed to to produce isoglycemic responses with 50 or 75 g oral glucose, ratios of integrated areas under concentration curves for immunoreactive C-peptide (CP) to insulin in the plasma were higher with IV than with oral glucose. Mean values +/- standard errors for these ratios in paired experiments with 50 g oral glucose were 5.6 +/- 0.66 compared with 8.3 +/- 1.4 with IV glucose (P < .03). With 75 g oral glucose, the corresponding values were 4.3 +/- 0.38 and 7.8 +/- 0.50 (P < .001). These results suggest that hepatic extraction of insulin is diminished when insulin secretion is potentiated by enteroinsular mechanisms after oral glucose administration. To determine whether this phenomenon is related to the route of administration of glucose or to the enhancement of insulin secretion with oral glucose, programmed IV infusions of glucose were used to elicit excursions of plasma CP similar to those obtained after 50 g oral glucose, and programmed infusions of glucose plus arginine were used to elicit excursions of plasma CP similar to those obtained after 75 g oral glucose. Plasma levels of immunoreactive gastric inhibitory polypeptide (GIP) increased substantially after ingestion of 75 g glucose, but did not change during isoglycemic IV glucose infusions or during IV infusions of glucose plus arginine.(ABSTRACT TRUNCATED AT 250 WORDS)

All bran vs corn flakes: plasma glucose and insulin responses in young females.

Plasma glucose and insulin responses to breakfasts containing all bran or corn flakes were determined in 11 normal female volunteers aged 21-27 y. The test meals provided 50 g egg, 133 g orange juice, 129 g 2% milk, 180 g coffee, 5 g margarine, and 30 g available carbohydrate from either all bran or corn flakes with 19 g or 1 g of dietary fiber, respectively. Plasma glucose and insulin responses were higher for the corn flake breakfast and the incremental area under the glucose curve was 40% greater than that for the all bran breakfast (t test, p less than 0.05). These results are consistent with the reported glycemic indices for these cereals when consumed alone but the glucose responses differ to a lesser degree when the cereals are ingested with other foods. Thus, in this group of well-defined subjects the effect of all bran and corn flakes on plasma glucose responses is attenuated when these cereals are incorporated into mixed meals.

Metabolic effects of continuous subcutaneous insulin infusion: evidence that a rise and fall of portal vein insulin concentration with each major meal facilitates post-absorptive glycemic control.

Eighteen lean adult volunteers with insulin-requiring diabetes mellitus attempted to achieve normoglycemia using continuous subcutaneous insulin infusion (CSII) or conventional insulin therapy (CIT) in a randomized crossover trial of 68 +/- 2.5 weeks (mean +/- SEM) duration. As reported (Diabetes Care 8: 447-55, 1985) the group with absent to low beta-cell function (C-peptide negative, n = 11) attained mean post-absorptive normoglycemia only during CSII vs CIT (p less than 0.05). Only following CSII was this without change in post-absorptive serum triglyceride concentrations (-4 +/- 5.6 vs 12 +/- 4.7 mg/dl; -0.04 +/- 0.6 vs 0.14 +/- 0.05 mM, p less than 0.05) or body weight (0.01 +/- 0.02 vs 0.05 +/- 0.01 kg/week, p less than 0.05). In the group with glucagon stimulated serum C-peptide 100-400 pmol/L (C-peptide positive) responses to CSII or CIT were equal. As total daily insulin dosage (0.05 +/- 0.04 U/kg/day) was the same under all conditions, to explain the efficacy of CSII, glucoregulatory hormone responses were examined. Pre- and post-test breakfast serum free immunoreactive insulin and plasma glucagon concentrations were essentially unaffected by C-peptide or treatment status. Erythrocyte 125I-insulin binding was decreased in the C-peptide negative group only during CSII (8.6 +/- 0.5 vs 10.1 +/- 0.7%, p less than 0.005); C-peptide positive group receptor binding was consistently low (8.2 +/- 0.8, 8.4 +/- 0.9%). During CIT using intermediate-acting insulin post-lunch peripheral venous insulin failed to rise (p less than 0.05), but in the C-peptide positive group, on the basis of C-peptide responses to breakfast an undetected rise and fall of portal venous insulin was assumed to coincide with each meal. Thus, only during CIT in the C-peptide negative group, which received on average 6.4/wk/subject fewer pre-meal regular insulin boluses (p less than 0.01), was the frequency of meal-related change in portal insulinemia decreased. Consistent meal-related fluctuations in portal insulinemia inherent in CSII hepatocytes sensitized by a post-receptor mechanism to the suppressive effects of insulin on glucose output and thus were indirectly responsible for the observed improvement in glycemic control and lipid metabolism in the C-peptide negative group.

Effect of cyclosporine on insulin binding to erythrocytes in type 1 diabetes mellitus of recent onset.

The effect of cyclosporine (Cyclosporin A) on insulin binding to erythrocytes was investigated in Type 1 diabetes mellitus of recent onset. The subjects were drawn from a pilot study (The Canadian Open Study on the effects of immunosuppression with Cyclosporine in Type 1 Diabetes Mellitus) in which 50% of the patients demonstrated remission during one year of cyclosporine administration. Specific binding of 125I-insulin was examined before and after 3, 6, or 12 months of cyclosporine in different groups of patients. Those who maintained target control of blood glucose without exogenous insulin for two or more weeks were designated non-insulin requiring. Basal and intravenous glucagon-stimulated immunoreactive plasma C-peptide rose in all groups but to higher levels in non-insulin requiring groups. Insulin binding at tracer concentration, reflecting the number of insulin receptors, was initially normal but tended to decrease with duration of cyclosporine administration. This decrease was significant especially in groups which remained insulin-requiring throughout the study. The affinity of erythrocyte receptors was assessed by determining the insulin concentration required for 50% inhibition of 125I-insulin binding, the ID50. These values suggested that the affinity of insulin receptors was not affected in subjects attaining non-insulin requiring remission; however, in subjects remaining dependent on exogenous insulin, receptor affinity appeared to be adversely affected. Even in subjects who demonstrated complete remission, affinity was decreased during periods of dependence on exogenous insulin. After discontinuation of cyclosporine for one month or more, the mean daily insulin dosage increased and plasma C-peptide decreased. Insulin binding at tracer concentration was not affected but the apparent affinity was decreased after withdrawal of cyclosporine. These results suggest that insulin action at the receptor may be affected by the administration of cyclosporine. The number of insulin receptors appears to be decreased but whether this effect has an impact on insulin sensitivity remains to be seen. Receptor affinity appears to be affected mainly by exogenous insulin. Thus immunosuppression with cyclosporine in newly diagnosed Type 1 diabetes mellitus may have a modest adverse effect on insulin receptors; whether the benefits of cyclosporine treatment outweigh this risk is difficult to assess.

Insulin-binding to erythrocytes in type I diabetes mellitus: effects of continuous subcutaneous infusion of insulin.

The binding of 125I-insulin was determined using erythrocytes obtained from 11 subjects with Type I diabetes mellitus treated with continuous subcutaneous infusions of insulin for 1 year or more. The binding characteristics were compared to those for erythrocytes isolated from 12 normal subjects and 10 subjects with Type I diabetes mellitus treated with conventional daily injections of insulin. The total binding of 125I-insulin, receptor concentration, and high and low affinity binding constants were estimated using washed erythrocytes obtained from fasted subjects. The mean total specific binding for subjects treated with continuous subcutaneous infusion did not differ from that for conventionally treated diabetic subjects but was slightly lower than that for normal subjects at p less than 0.05. Receptor concentration did not vary significantly between the groups. High and low affinity binding constants were slightly lower in the group treated with continuous subcutaneous infusion. Both basal and diurnal plasma levels of free immunoreactive insulin were slightly but significantly elevated in both groups of diabetic subjects compared to that in normal subjects. Thus, in spite of the greater biological effectiveness of the continuous insulin infusion program in terms of glycemic control, the insulin-binding parameters, as well as the estimates of plasma free immunoreactive insulin levels, are consistent with modest and comparable degrees of hyperinsulinemia with both treatments.