Oral vanadyl sulfate improves hepatic and peripheral insulin sensitivity in patients with non-insulin-dependent diabetes mellitus.

We examined the in vivo metabolic effects of vanadyl sulfate (VS) in non-insulin-dependent diabetes mellitus (NIDDM). Six NIDDM subjects treated with diet and/or sulfonylureas were examined at the end of three consecutive periods: placebo for 2 wk, VS (100 mg/d) for 3 wk, and placebo for 2 wk. Euglycemic hyperinsulinemic (30 mU/m2.min) clamps and oral glucose tolerance tests were performed at the end of each study period. Glycemic control at baseline was poor (fasting plasma glucose 210 +/- 19 mg/dl; HbA1c 9.6 +/- 0.6%) and improved after treatment (181 +/- 14 mg/dl [P < 0.05], 8.8 +/- 0.6%, [P < 0.002]); fasting and post-glucose tolerance test plasma insulin concentrations were unchanged. After VS, the glucose infusion rate during the clamp was increased (by approximately 88%, from 1.80 to 3.38 mg/kg.min, P < 0.0001). This improvement was due to both enhanced insulin-mediated stimulation of glucose uptake (rate of glucose disposal [Rd], +0.89 mg/kg.min) and increased inhibition of HGP (-0.74 mg/kg.min) (P < 0.0001 for both). Increased insulin-stimulated glycogen synthesis (+0.74 mg/kg.min, P < 0.0003) accounted for > 80% of the increased Rd after VS, and the improvement in insulin sensitivity was maintained after the second placebo period. The Km of skeletal muscle glycogen synthase was lowered by approximately 30% after VS treatment (P < 0.05). These results indicate that 3 wk of treatment with VS improves hepatic and peripheral insulin sensitivity in insulin-resistant NIDDM humans. These effects were sustained for up to 2 wk after discontinuation of VS.

Regulation of endogenous glucose production by glucose per se is impaired in type 2 diabetes mellitus.

We examined the ability of an equivalent increase in circulating glucose concentrations to inhibit endogenous glucose production (EGP) and to stimulate glucose metabolism in patients with Type 2 diabetes mellitus (DM2). Somatostatin was infused in the presence of basal replacements of glucoregulatory hormones and plasma glucose was maintained either at 90 or 180 mg/dl. Overnight low-dose insulin was used to normalize the plasma glucose levels in DM2 before initiation of the study protocol. In the presence of identical and constant plasma insulin, glucagon, and growth hormone concentrations, a doubling of the plasma glucose levels inhibited EGP by 42% and stimulated peripheral glucose uptake by 69% in nondiabetic subjects. However, the same increment in the plasma glucose concentrations failed to lower EGP, and stimulated glucose uptake by only 49% in patients with DM2. The rate of glucose infusion required to maintain the same hyperglycemic plateau was 58% lower in DM2 than in nondiabetic individuals. Despite diminished rates of total glucose uptake during hyperglycemia, the ability of glucose per se (at basal insulin) to stimulate whole body glycogen synthesis (glucose uptake minus glycolysis) was comparable in DM2 and in nondiabetic subjects. To examine the mechanisms responsible for the lack of inhibition of EGP by hyperglycemia in DM2 we also assessed the rates of total glucose output (TGO), i.e., flux through glucose-6-phosphatase, and the rate of glucose cycling in a subgroup of the study subjects. In the nondiabetic group, hyperglycemia inhibited TGO by 35%, while glucose cycling did not change significantly. In DM2, neither TGO or glucose cycling was affected by hyperglycemia. The lack of increase in glucose cycling in the face of a doubling in circulating glucose concentrations suggested that hyperglycemia at basal insulin inhibits glucose-6-phosphatase activity in vivo. Conversely, the lack of increase in glucose cycling in the presence of hyperglycemia and unchanged TGO suggest that the increase in the plasma glucose concentration failed to enhance the flux through glucokinase in DM2. In summary, both lack of inhibition of EGP and diminished stimulation of glucose uptake contribute to impaired glucose effectiveness in DM2. The abilities of glucose at basal insulin to both increase the flux through glucokinase and to inhibit the flux through glucose-6-phosphatase are impaired in DM2. Conversely, glycogen synthesis is exquisitely sensitive to changes in plasma glucose in patients with DM2.

Increased epinephrine and skeletal muscle responses to hypoglycemia in non-insulin-dependent diabetes mellitus.

We evaluated skeletal muscle counterregulation during hypoglycemia in nine subjects with non-insulin-dependent diabetes mellitus (NIDDM) (HbA1c 9.4 +/- 0.5%, nl < 6.2%) compared with six normal controls, matched for age (51 +/- 3 and 49 +/- 5 yr, respectively) and body mass index (27.3 +/- 1.2 and 27.0 +/- 2.1 kg/m2). After 60 min of euglycemia (plasma insulin approximately 140 microU/ml), plasma glucose was lowered to 62 +/- 2 mg/dl by 120 min. Hypoglycemia induced a 2.2-fold greater increase in plasma epinephrine in NIDDM (P < 0.001), while the plasma glucagon response was blunted (P < 0.01). Hepatic glucose output ([3H-3]glucose) suppressed similarly during euglycemia, but during hypoglycemia was greater in NIDDM (P < 0.005). Conversely, glucose uptake during euglycemia was 150% greater in controls (P < 0.01) and remained persistently higher than in NIDDM during hypoglycemia. In NIDDM, plasma FFA concentrations were approximately fivefold greater (P < 0.001), and plasma lactate levels were approximately 40% higher than in controls during hypoglycemia (P < 0.01); the rates of glycolysis from plasma glucose were similar in the two groups despite a 49% lower rate of glucose uptake in NIDDM (3.4 +/- 0.9 vs. 6.9 +/- 1.3 mg/kg per minute, P < 0.001). Muscle glycogen synthase activity fell by 42% with hypoglycemia (P < 0.01) in NIDDM but not in controls. In addition, glycogen phosphorylase was activated by 56% during hypoglycemia in NIDDM only (P < 0.01). Muscle glucose-6-phosphate concentrations rose during hypoglycemia by a twofold greater increment in NIDDM (P < 0.01). Thus, skeletal muscle participates in hypoglycemia counterregulation in NIDDM, directly by decreased removal of plasma glucose and, indirectly, by providing lactate for hepatic gluconeogenesis. Consequently, in addition to inherent insulin resistance in NIDDM, the enhanced plasma epinephrine response during hypoglycemia may partially offset impaired glucagon secretion and counteract the effects of hyperinsulinemia on liver, fat, and skeletal muscle.

Impaired counterregulation of hypoglycemia in insulin-dependent diabetes mellitus.

We evaluated the recovery of blood glucose after insulin-induced hypoglycemia in six insulin-dependent diabetics (insulin-infused and initially euglycemic) and six normal controls after comparable reductions in plasma glucose. In contrast to controls, the recovery of plasma glucose was delayed in diabetics (2-h plasma glucose 80 +/- 5 mg/dl and 58 +/- 5 mg/dl, respectively, P less than 0.01). This delay was due to the absence of a rebound in hepatic glucose output in the diabetics, whereas glucose output rose two- to threefold above baseline in normals. The impaired rebound in glucose output in diabetics could not be attributed to hyperinsulinemia. Rather, hypoglycemia-induced secretion of epinephrine and glucagon was reduced in the diabetics by 60-80% as compared with normals (P less than 0.001). The diabetics did not suffer from overt neuropathy and plasma cortisol, growth hormone, and norepinephrine increased normally following hypoglycemia. The data suggest that prolonged hypoglycemia may frequently occur in tightly controlled type I diabetics because of impaired rebound in hepatic glucose release which in turn may be a consequence of reduced secretion of epinephrine and glucagon.

Defective epinephrine and growth hormone responses in type I diabetes are stimulus specific.

The counterregulatory hormone responses to hypoglycemia and a non-glucose stimulus, exercise, were evaluated in 18 subjects with type I diabetes and in 9 normal controls. Subjects with diabetes had no overt neuropathy, with R-R variations and postural plasma norepinephrine increments that were similar to those of controls. The diabetic subjects exhibited normal increments in plasma growth hormone (GH), norepinephrine, and cortisol but blunted or absent responses in plasma epinephrine and glucagon when hypoglycemia was severe (less than 40 mg/dl). During a 60-min clamped reduction in plasma glucose at approximately 65 mg/dl, plasma GH and epinephrine increased 6- to 15-fold in controls but 2- to 4-fold in diabetics (P less than .05). However, when subjects were exercised at this plasma glucose level (50 W for 10 min), plasma epinephrine and GH in diabetics rose markedly by 150-400% to attain the peaks reached by the controls. Plasma norepinephrine and cortisol increased to similar levels in both groups, and plasma glucagon was not significantly changed. We conclude that epinephrine and GH secretion in response to hypoglycemia are reduced in type I diabetes but that these defects are stimulus specific because the responses to exercise are not reduced.

Further defects in counterregulatory responses induced by recurrent hypoglycemia in IDDM.

We evaluated the effect of previous experimental hypoglycemia on counterregulatory responses to hypoglycemia in 13 IDDM patients. These patients had defects in counterregulatory responses to hypoglycemia compared with 7 nondiabetic control subjects. Plasma EPI and glucagon responses to hypoglycemia in IDDM patients were approximately 60% of levels in nondiabetic subjects (P less than 0.02 and P less than 0.001, respectively). Hepatic glucose output ([3-3H]glucose) was reduced by approximately 60% of normal (P less than 0.005), and the glucose infusion rate required to maintain plasma glucose was correspondingly greater in people with IDDM (P less than 0.001). With a modified glucose clamp (plasma insulin approximately 330 pM), the diabetic subjects underwent two sequential 120-min periods of hypoglycemia (approximately 3.0 mM) with an intervening 60-min euglycemic recovery period. In the IDDM patients, there were 30-50% decreases in plasma GH (P less than 0.005) and cortisol (P less than 0.001) responses during the second hypoglycemic period compared with the first. In addition, glucose output, already defective compared with that in nondiabetic subjects, was further reduced by 33% (P = 0.03) during the second period of experimental hypoglycemia. There was no effect of repeated hypoglycemia on the responses of plasma glucagon, EPI, or NE, though plasma EPI was correlated directly with glucose output (P less than 0.001) and inversely with glucose uptake (P less than 0.05). There was no correlation between the rise in glucose output during hypoglycemia and antecedent glycemic control as measured by HbA1.(ABSTRACT TRUNCATED AT 250 WORDS)

Epinephrine-induced hypoaminoacidemia in normal and diabetic human subjects: effect of beta blockade.

To evaluate the effect of epinephrine on the circulating amino acids, we infused epinephrine into normal human subjects and juvenile-onset diabetic patients given a constant basal infusion of insulin. Epinephrine infusion produced an identical 350--400 pg/ml rise in plasma epinephrine in both groups. In normal subjects, epinephrine caused a progressive 26% reduction in total circulating amino acids, despite unchanged levels of plasma insulin. This effect was most pronounced for the branched amino acids, which fell by 40% (P < 0.001). Plasma alanine was the only amino acid which failed to decline. Similarly, infusion of epinephrine in the insulin-infused diabetics produced a 23% fall in total amino acids, a 37% decline in branched chain amino acids, but no change in plasma alanine. Saline infusion in the insulin-infused diabetics had no effect on plasma amino acid concentrations. In addition, when epinephrine was infused into two insulin-withdrawn diabetics, a comparable hypoaminoacidemic response was observed. The infusion of propranolol in both normal and diabetic subjects totally prevented the epinephrine-induced fall in plasma amino acids. It is concluded that (1) increments in epinephrine similar to those observed in stress cause a decline in circulating amino acids (except alanine) which is greatest for the branched chain amino acids; (2) this hypoaminoacidemic effect occurs in the absence of a rise in plasma insulin and diabetic subjects, as well; and (3) epinephrine-induced changes in amino acid regulation are prevented by beta-adrenergic blockade. Our findings suggest that, in contrast with glucose and fat metabolism, epinephrine and insulin may have similar, rather than antagonistic, effects on plasma amino acid metabolism.

Counterregulation of hypoglycemia. Skeletal muscle glycogen metabolism during three hours of physiological hyperinsulinemia in humans.

We examined the role of skeletal muscle in counterregulation of hypoglycemia (3.4 +/- 0.1 mmol/l) in 12 nondiabetic individuals (age 26 +/- 1 years, body mass index 24.2 +/- 0.7 kg/m2) during physiological hyperinsulinemia (280 +/- 25 pmol/l) compared with euglycemia (4.8 +/- 0.1 mmol/l). During hypoglycemia, hepatic glucose output (3-[3H]-glucose) was greater (7.72 +/- 2.72 mumol.kg-1.min-1, P < 0.01), glucose uptake was approximately 49% lower (21.20 +/- 3.55 mumol.kg-1.min-1, P < 0.005), and glucose clearance was reduced (P < 0.002) compared with euglycemia. Rates of flux of plasma-derived glucosyl units through glycolysis were similar in the two experiments, while glycogen synthetic rates were significantly reduced during hypoglycemia (P < 0.01) and accounted entirely for the reduction in glucose disposal. The insulin-induced activation of skeletal muscle glycogen synthase (reflected by Km decline by approximately 50% from 0.408 +/- 0.056 mmol/l and fractional velocity increase by approximately twofold from 21.8 +/- 2.7%) was completely abolished in hypoglycemia. In concert, glycogen phosphorylase activity increased during hypoglycemia by approximately 40% (P = 0.0001). Hypoglycemia resulted in seven- to eightfold increments in plasma epinephrine (P < 0.0001) and growth hormone (P < 0.001) and 40-60% increments in plasma glucagon (P < 0.005) and cortisol (P < 0.05). We conclude that, in this model of mild hypoglycemia of moderate duration, the majority of the glucose made available during the counterregulatory process (approximately 60-70%) is due to the limitation of glucose disposal, mostly via decreased glycogen synthetic activity in skeletal muscle.

Oral vanadyl sulfate improves insulin sensitivity in NIDDM but not in obese nondiabetic subjects.

We compared the effects of oral vanadyl sulfate (100 mg/day) in moderately obese NIDDM and nondiabetic subjects. Three-hour euglycemic-hyperinsulinemic (insulin infusion 30 mU / m / min) clamps were performed after 2 weeks of placebo and 3 weeks of vanadyl sulfate treatment in six nondiabetic control subjects (age 37 +/- 3 years; BMI 29.5 +/- 2.4 kg/m2 ) and seven NIDDM subjects (age 53 +/- 2 years; BMI 28.7 +/-1.8 kg/m2). Glucose turnover ([3-3 H]glucose), glycolysis from plasma glucose, glycogen synthesis, and whole-body carbohydrate and lipid oxidation were evaluated. Decreases in fasting plasma glucose (by approximately 1.7 mmol/l) and HbAlc (both P < 0.05) were observed in NIDDM subjects during treatment; plasma glucose was unchanged in control subjects. In the latter, the glucose infusion rate (GIR) required to maintain euglycemia (40.1 +/- 5.7 and 38.1 +/- 4.8 micromol / kg fat-free mass FFM / min) and glucose disposal (Rd) (41.7 +/- 5.7 and 38.9 +/-4.7 micromol / kg FFM / min were similar during placebo and vanadyl sulfate administration, respectively. Hepatic glucose output (HGO) was completely suppressed in both studies. In contrast, in NIDDM subjects, vanadyl sulfate increased GIR approximately 82% (17.3 +/- 4.7 to 30.9 +/- 2.7 micromol / kg FFM / min, P < 0.05); this improvement in insulin sensitivity was due to both augmented stimulation of Rd (26.0 +/-4.0 vs. 33.6 +/- 2.22 micromol / kg FFM / min, P < 0.05) and enhanced suppression of HGO (7.7 +/- 3.1 vs. 1.3 +/- 0.9 micromol / kg FFM / min, P < 0.05). Increased insulin-stimulated glycogen synthesis accounted for >80% of the increased Rd with vanadyl sulfate (P < 0.005), but plasma glucose flux via glycolysis was unchanged. In NIDDM subjects, vanadyl sulfate was also associated with greater suppression of plasma free fatty acids (FFAs) (P < 0.01) and lipid oxidation (P < 0.05) during clamps. The reduction in HGO and increase in Rd were both highly correlated with the decline in plasma FFA concentrations during the clamp period (P < 0.001). In conclusion, small oral doses of vanadyl sulfate do not alter insulin sensitivity in nondiabetic subjects, but it does improve both hepatic and skeletal muscle insulin sensitivity in NIDDM subjects in part by enhancing insulin's inhibitory effect on lipolysis. These data suggest that vanadyl sulfate may improve a defect in insulin signaling specific to NIDDM.

Relationship of insulin secretion and glycemic response to dietary intervention in non-insulin-dependent diabetes.

Forty-two obese subjects with non-insulin-dependent diabetes mellitus had their plasma insulin, C peptide, and glucose levels measured after an overnight fast and in response to a 75-g oral glucose loading. Subjects were then prospectively followed up with dietary treatment, and the same measurements were repeated at 1 year. Although insulin values tended to be lower with greater fasting hyperglycemia at baseline, no correlation was observed among three parameters. However, near-normalization of glycemia (measured as the level of hemoglobin A1) was associated with significantly higher fasting and stimulated plasma insulin concentrations. Sixteen subjects were matched to each other for equivalent baseline hyperglycemia (by glycosylated hemoglobin) and divided into group 1 (normalization of the hemoglobin A1 value to 7.0% +/- 0.3% [mean +/- SE]) and group 2 (persistent hyperglycemia) (hemoglobin A1 value, 10.7% +/- 0.7% [mean +/- SE]). Before dietary therapy, the plasma insulin concentrations were twofold to threefold higher in group 1, and despite similar degrees of weight loss, group 2 failed to demonstrate improved glycemia. We concluded that the outcome of diet therapy for non-insulin-dependent diabetes mellitus is dependent on the duration of diabetes and endogenous insulin secretory reserve. There is a subgroup of patients with non-insulin-dependent diabetes mellitus in whom delayed dietary intervention may have a beneficial effect.

Effect of propranolol on delayed glucose recovery after insulin-induced hypoglycemia in normal and diabetic subjects.

In order to evaluate the influence of beta-adrenergic blockade on recovery from insulin-induced hypoglycemia, we compared the effect of saline or propranolol infusion during concomitant hypoglycemia in normal and type I diabetic persons. The diabetic subjects were initially rendered euglycemic with a basal insulin infusion. Glucose turnover was measured using [3-3H]glucose tracer. Propranolol caused a small but significant delay in glucose recovery in normal subjects, with plasma glucose only 80% of the values seen during saline infusion 1 h after hypoglycemia (P less than 0.005). This delay was caused by a 70% reduction in the rebound glucose output, which was responsible for posthypoglycemic recovery. In the diabetic subjects, glucose recovery was significantly delayed as compared with that in normal persons, even in the absence of propranolol, and associated with reduced secretion of epinephrine and glucagon. Moreover, the addition of propranolol caused a further 50% reduction in glucose recovery such that plasma glucose remained below 50 mg/dl for 3 h. In contrast to normals, propranolol did not inhibit the already blunted rebound in glucose output. However, propranolol prevented the decline in glucose utilization that occurred when saline alone was infused. During saline infusion, glucose uptake was at basal rates by 60 min whereas, during propranolol administration, glucose uptake remained above baseline until 180 min (P less than 0.01). Thus, propranolol may interfere with glucose recovery after insulin-induced hypoglycemia in diabetic patients by blocking epinephrine's inhibition of glucose utilization whereas, in normals, propranolol's effect is largely accounted for by blockade of epinephrine-induced hepatic glucose production.

Quality assurance for blood glucose monitoring in health-care facilities.

OBJECTIVE: To describe the practice of quality assurance (QA) for capillary blood glucose monitoring (CBGM) in health-care facilities. RESEARCH DESIGN AND METHODS: Descriptive survey data were collected from a purposive sample of 378 health-care providers, who use CBGM and direct CBGM QA programs, from acute- and chronic-care facilities in 47 states. Subjects completed a 36-item multiple-choice survey about QA practices for CBGM by providers. RESULTS: Only 53.4% of respondents reported a multidisciplinary advisory group to assist in decision making for the CBGM program. Almost one-third reported no clinical laboratory involvement in their QA program. Over 70% of respondents reported inclusion of all clinical areas in the CBGM program. Comparison of results of the same patient sample by laboratory reference method and CBGM system was done routinely by only 43.6% of respondents. Scheduled proficiency testing was reported by 33.4%. Only 5.8% of respondents reported the coexistence of a CBGM advisory group, full participation of the laboratory, and quarterly proficiency testing. Over 50% of respondents reported a patient charge for CBGM. CONCLUSIONS: When survey results are compared with regulatory and accreditation standards, it is evident that a wide gap exists. Resources to bridge this gap may be scarce in many facilities. Further research is needed to determine minimal QA standards for CBGM that provide for optimal patient outcomes.

Psychological and social correlates of glycemic control.

Eighty-four persons with insulin-dependent diabetes participated in this study to determine whether glycemic control was related to personality, anxiety, depression, and/or quality of life. The subjects were placed on either a conventional treatment regimen consisting of one to two injections of mixed short- and intermediate-acting insulin, with urine testing or an intensive treatment regimen consisting of two or more injections of mixed insulins, with self-monitoring of blood glucose. Personality was found to have no relationship to level of glycemic control either at the beginning of the study or at any point during the study. In contrast, anxiety, depression, and quality of life showed a significant relationship to metabolic control at entry and throughout the study period. Lower anxiety and depression scores and better quality of life scores were recorded for those subjects in good control (HbA1 less than 8.9%) when compared with those in average control (HbA1 9.0-11.9%) and those in poor control (HbA1 greater than 11.9%) at entry (P = 0.01). At each point during the study the difference between those in good control and those in poor control in terms of anxiety, depression, and quality of life was significant (P = 0.02). Change in glycemic control was found to account for up to 20% of the between-patient variability for these psychosocial parameters.

Effect of antecedent hypoglycemia on cognitive function and on glycemic thresholds for counterregulatory hormone secretion in healthy humans.

OBJECTIVE: To determine whether reduced hormonal, symptomatic, and/or cognitive responses to hypoglycemia are caused by an increase in the plasma glucose concentration required to stimulate these counterregulatory parameters after antecedent hypoglycemia. RESEARCH DESIGN AND METHODS: We studied nine healthy volunteers during stepped hypoglycemia clamps (plasma glucose targets from 80 to 50 mg/dl in 10 mg/dl steps) on two separate days. The study was preceded either by a 2-h period of hypoglycemia (plasma glucose 58 +/- 2 mg/dl) or a 2-h period of euglycemia (plasma glucose 94 +/- 2 mg/dl) for 90 min. RESULTS: The plasma glucose that triggered secretion of plasma norepinephrine (NE) was lower after antecedent hypoglycemia (control = 74 +/- 2 and experimental = 67 +/- 2 mg/dl, respectively, P < 0.005). In contrast, a relatively higher plasma glucose stimulated secretion of other counterregulatory hormones after antecedent hypoglycemia: growth hormone (GH) (65 +/- 2 to 72 +/- 2 mg/dl, P < 0.01); glucagon (63 +/- 2 to 70 +/- 2 mg/dl, P < 0.01); and epinephrine (EPI) (68 +/- 2 to 76 +/- 2 mg/dl, P < 0.01) when comparing control days with experimental days. Hypoglycemic symptoms were first observed at a plasma glucose plateau of 59 +/- 2 mg/dl. Motor function reflected by Digit Symbol Substitution deteriorated equally whether there had been antecedent hypoglycemia or euglycemia. Logical (immediate) memory deteriorated in the control study at a plasma glucose of 54 +/- 2 mg/dl but remained unchanged at equivalent hypoglycemia in the experimental study (P < 0.03). CONCLUSIONS: Our conclusions are as follows: 1) symptoms of moderate hypoglycemia occur at plasma glucose levels averaging approximately 5-15 mg/dl lower than the plasma glucose concentrations required to trigger counterregulatory hormone release; 2) after acute antecedent hypoglycemia, glucagon, EPI, and GH secretion occur at higher plasma glucose concentrations and NE is released at lower plasma glucose concentrations; and 3) there may be CNS adaptation to prior hypoglycemia reflected in preservation of logical memory function at plasma glucose levels of approximately 50 mg/dl. These findings suggest that thresholds for hormone secretion and for changes in cognitive function can be altered very acutely by foregoing hypoglycemia in healthy humans.

Self-monitoring of capillary blood glucose: changing the performance of individuals with diabetes.

Standard reflectance meters were modified by the addition of memory chips capable of storing 440 glucose determinations with corresponding time and date. These modified reflectance meters (MR) were given to 20 individuals with type I diabetes in an effort to determine the level of reliability and accuracy they could achieve on a self-monitoring regimen. During a 6-wk period these subjects measured their capillary blood glucose and recorded the results in a logbook (LB). At 2-wk intervals they visited the clinic. Data from the MR was offloaded onto an Apple IIe microcomputer (Apple Computer, Inc., Cupertino, California) and presented to the subjects in a graphic format, depicting the level of metabolic control over the previous 2 wk. The performance of subjects for the 6-wk period showed that they averaged 7 omissions from the LB for every 100 MR recordings; 1 added value in the LB for every 200 MR recordings; and 1 error in accurately copying the test value for every 100 determinations. In comparison with subjects who participated in an earlier study in which they were unaware of the memory function of the reflectance meter, performance during the current study improved in all categories. It was also observed that consistency in reliable and accurate record keeping did not diminish throughout the study period. Despite these positive changes in performance, no alteration in glycemic control was found.

Transcutaneous glucose measurement using near-infrared spectroscopy during hypoglycemia.

OBJECTIVE: To analyze a transcutaneous near-infrared spectroscopy system as a technique for in vivo noninvasive blood glucose monitoring during euglycemia and hypoglycemia. RESEARCH DESIGN AND METHODS: Ten nondiabetic subjects and two patients with type 1 diabetes were examined in a total of 27 studies. In each study, the subject's plasma glucose was lowered to a hypoglycemia level (approximately 55 mg/dl) followed by recovery to a glycemic level of approximately 115 mg/dl using an intravenous infusion of insulin and 20% dextrose. Plasma glucose levels were determined at 5-min intervals by standard glucose oxidase method and simultaneously by a near-infrared spectroscopic system. The plasma glucose measured by the standard method was used to create a calibration model that could predict glucose levels from the near-infrared spectral data. The two data sets were correlated during the decline and recovery in plasma glucose, within 10 mg/dl plasma glucose ranges, and were examined using the Clarke Error Grid Analysis. RESULTS: Two sets of 1,704 plasma glucose determinations were examined. The near-infrared predictions during the fall and recovery in plasma glucose were highly correlated (r = 0.96 and 0.95, respectively). When analyzed during 10 mg/dl plasma glucose segments, the mean absolute difference between the near-infrared spectroscopy method and the chemometric reference ranged from 3.3 to 4.4 mg/dl in the nondiabetic subjects and from 2.6 to 3.8 mg/dl in the patients with type 1 diabetes. Using the Error Grid Analysis, 97.7% of all the near-infrared predictions were assigned to the A-zone. CONCLUSIONS: Our findings suggest that the near-infrared spectroscopy method can accurately predict plasma glucose levels during euglycemia and hypoglycemia in humans.

Efficacy, safety, and dose-response characteristics of glipizide gastrointestinal therapeutic system on glycemic control and insulin secretion in NIDDM. Results of two multicenter, randomized, placebo-controlled clinical trials. The Glipizide Gastrointestinal Therapeutic System Study Group.

OBJECTIVE: To investigate the efficacy, safety, and dose-response characteristics of an extended-release preparation of glipizide using the gastrointestinal therapeutic system (GITS) on plasma glucose, glycosylated hemoglobin (HbA1c), and insulin secretion to a liquid-mixed meal in NIDDM patients. RESEARCH DESIGN AND METHODS: Two prospective, randomized, double-blind, placebo-controlled, multicenter clinical trials were performed in 22 sites and 347 patients with NIDDM (aged 59 +/- 0.6 years; BMI, 29 +/- 0.3 kg/m2; known diabetes duration, 8 +/- 0.4 years) were studied. Each clinical trial had a duration of 16 weeks with a 1-week washout, 3-week single-blind placebo phase, 4-week titration to a fixed dose, and 8-week maintenance phase at the assigned dose. In the first trial, once-daily doses of 5, 20, 40, or 60 mg glipizide GITS were compared with placebo in 143 patients. In the second trial, doses of 5, 10, 15, or 20 mg of glipizide GITS were compared with placebo in 204 patients. HbA1c, fasting plasma glucose (FPG), insulin, C-peptide, and glipizide levels were determined at regular intervals throughout the study. Postprandial plasma glucose (PPG), insulin, and C-peptide also were determined at 1 and 2 h after a mixed meal (Sustacal). RESULTS: All doses of glipizide GITS in both trials produced significant reductions from placebo in FPG (range -57 to -74 mg/dl) and HbA1c (range -1.50 to -1.82%). Pharmacodynamic analysis indicated a significant relationship between plasma glipizide concentration and reduction in FPG and HbA1c over a dose range of 5-60 mg, with maximal efficacy achieved at a dose of 20 mg for FPG and at 5 mg for HbA1c. PPG levels were significantly lower, and both postprandial insulin and C-peptide levels significantly higher in patients treated with glipizide GITS compared with placebo. The percent reduction in FPG was comparable across patients with diverse demographic and clinical characteristics, including those with entry FPG > or = 250 mg/dl, resulting in greater absolute decreases in FPG and HbA1c in patients with the most severe hyperglycemia. Despite the forced titration to a randomly assigned dose, only 11 patients in both studies discontinued therapy because of hypoglycemia. Glipizide GITS did not alter lipids levels or produce weight gain. CONCLUSIONS: The once-daily glipizide GITS 1) lowered HbA1c, FPG, and PPG over a dose range of 5-60 mg, 2) was maximally effective at 5 mg (using HbA1c) or 20 mg (using FPG) based on pharmacokinetic and pharmacodynamic relationships, 3) maintained its effectiveness in poorly controlled patients (those with entry FPG > or = 250 mg/dl), 4) was safe and well tolerated in a wide variety of patients with NIDDM, and 5) did not produce weight gain or adversely affect lipids.

Selective counterregulatory hormone responses after oral glucose in man.

The plasma response of various counterregulatory hormones was measured after an oral glucose tolerance test in 19 normal subjects. Significant elevations in plasma epinephrine (P less than 0.05) and human GH (P less than 0.05) were observed late in the course of the oral glucose tolerance test coincident with the fall in plasma glucose. Plasma norepinephrine, glucagon, and cortisol levels did not change during the latter phase of the test. The elevations in plasma human GH and epinephrine levels were unrelated to either absolute hypoglycemia or to clinical symptoms of hypoglycemia. These data suggest a possible role for adrenergic mechanisms in glucose counterregulation under physiological conditions.

Counterregulatory adaptation to recurrent hypoglycemia in normal humans.

We evaluated the effect of antecedent hypoglycemia on glucose counterregulation during hypoglycemia in non-diabetic human subjects. In single hypoglycemia studies, glucose production [( 3H]3-glucose) and counterregulatory hormone concentrations were measured (after a 3.5-h baseline period of euglycemia) during 120 min of hypoglycemia (glucose clamped at 3.0 mmol/L). During the final 60 min of hypoglycemia, counterregulation resulted in significant increments in glucose production (12.88 +/- 0.83 mumol/kg.min), and plasma glucagon (IRG; 185 +/- 22 ng/L), GH (29.3 +/- 7.0 micrograms/L), cortisol (630 +/- 100 nmol/L), epinephrine (3.44 +/- 0.76 nmol/L), and norepinephrine (2.02 +/- 0.21 nmol/L). In the recurrent hypoglycemia experiment, an antecedent period of identical hypoglycemia was induced. Glucose counterregulation during the second of two periods of hypoglycemia (HYPO 2) was then compared to that in single hypoglycemia studies. During HYPO 2, there were decreased responses in Ra (by 32%; P less than 0.03), GH (by 67%; P less than 0.05), F (by 41%; P less than 0.03), and norepinephrine (by 20%; P = 0.03) compared to those in the single hypoglycemia study. In contrast, plasma IRG values were similar in the single hypoglycemia studies and HYPO 2, but were reduced relative to those during the first hypoglycemic period of recurrent hypoglycemia (IRG, 263 +/- 18 ng/L; P less than 0.025 vs. HYPO 2 and P less than 0.05 vs. single hypoglycemia). Our results suggest that 1) antecedent hypoglycemia may alter glucose counterregulation during hypoglycemia; and 2) recurrent hypoglycemia may result in alterations in reduction of hepatic glucose production.

Deficient counterregulatory hormone responses during hypoglycemia in a patient with insulinoma.

Counterregulatory hormone responses were evaluated in a 37-yr-old woman before and after removal of a benign insulin-producing islet cell tumor. Counterregulatory hormone concentrations were measured during a glucose clamp with graded reductions of plasma glucose from 5.2 to 2.6 mmol/L. In the study before surgery, the increase in plasma epinephrine concentration was markedly blunted (by greater than 90%) compared to that in the study after surgery. The peak plasma norepinephrine concentration was similarly reduced by 71%, and plasma cortisol by 63%. In addition, the glycemic thresholds for secretion of the counterregulatory hormones were lower before removal of the tumor. Peak plasma GH responses were equivalent before and after surgery, but the threshold for GH secretion was 21% lower in the first hypoglycemia study. We conclude 1) that there is evidence for abnormal glucose counterregulatory hormone secretion in this patient, which may contribute to the pathogenesis of hypoglycemia seen in patients with insulinoma; 2) the reversal of reduced counterregulatory hormone secretion after tumor resection suggests that these defective hormonal responses may be related to recurrent hypoglycemia, persistent hyperinsulinemia, or both; and 3) that abnormal glucose counterregulation may exist in the absence of type 1 diabetes.