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D C Simonson

Publications and source records attributed to D C Simonson.

At least 37 records · Page 2Linked to original sources

Cognitive function in patients with insulin-dependent diabetes mellitus during hyperglycemia and hypoglycemia.

BACKGROUND: To determine the impact of glycemic control, gender, and other relevant parameters on cognitive function during exposure to different blood glucose levels in patients with insulin-dependent diabetes mellitus (IDDM), we examined neuropsychologic function during experimentally induced periods of hyperglycemia and hypoglycemia. METHODS: We studied 20 men and 22 women, aged 18 to 44 years, with IDDM duration of 3 to 14 years and HbA1 values ranging from 5.8% to 18.0% (nondiabetic range 5.4% to 7.4%). We used a controlled experimental setting involving tests of sensory perceptual processing, simple motor abilities, attention, learning and memory, language, and spatial and constructional abilities at plasma glucose levels of 2.2, 5.6, 8.9, 14.4, and 21.1 mmol/L. Patients were blind to the glucose level. Tests used at each glucose level included reaction time (simple and choice), digit vigilance, trail making part B, word recall, digit sequence learning, and verbal fluency. RESULTS: All aspects of neuropsychologic function were diminished at 2.2 mmol/L when compared with basal levels of performance at 8.9 mmol/L, whereas no alterations were observed at 14.4 or 21.1 mmol/L. Tests involving associative learning, attention, and mental flexibility were the most affected during hypoglycemia. Glycemic control was not correlated with neuropsychologic function at any glucose level. Women demonstrated less of an impairment in neuropsychologic function than men at 2.2 mmol/L. CONCLUSIONS: Cognitive function in IDDM patients was generally well-preserved even at substantially elevated blood glucose levels. Deficits in all relevant areas of cognitive function occurred during hypoglycemia (2.2 mmol/L), irrespective of prior glycemic control, and women with IDDM were less cognitively impaired than men with IDDM during hypoglycemia.

Adult↗

Metabolic effects of sodium metavanadate in humans with insulin-dependent and noninsulin-dependent diabetes mellitus in vivo and in vitro studies.

To investigate the efficacy and mechanism of action of sodium metavanadate as an oral hypoglycemic agent, five insulin-dependent diabetes mellitus (IDDM) and five noninsulin-dependent diabetes mellitus (NIDDM) patients were studied before and after 2 weeks of oral sodium metavanadate (NaVO3; 125 mg/day). Glucose metabolism measured during a two-step euglycemic insulin clamp was not significantly increased by vanadate therapy in patients with IDDM, but was improved by 29% during the low dose (0.5 mU/kg.min) insulin infusion and 39% during the high dose (1.0 mU/kg.min) in patients with NIDDM. The changes in glucose metabolism were largely accounted for by an increase in nonoxidative glucose disposal, as measured by indirect calorimetry. Basal hepatic glucose production and suppression of hepatic glucose production by insulin were unchanged by vanadate therapy. There was a significant decrease in insulin requirements in the patients with IDDM (39.1 +/- 6.6 to 33.8 +/- 4.7 U/day; P < 0.05). Cholesterol levels significantly decreased in both IDDM (4.53 +/- 0.16 vs. 4.27 +/- 0.22 mmol/L; P = 0.06) and NIDDM (6.92 +/- 0.75 vs. 5.28 +/- 0.46 mmol/L; P < 0.05). After NaVO3 therapy, there was a 1.7- to 3.9-fold increase in basal mitogen-activated protein and S6 kinase activities in mononuclear cells from patients with IDDM and NIDDM that mimicked the effect of insulin stimulation in controls. The most common adverse effect of oral NaVO3 was mild gastrointestinal intolerance. These data suggest that vanadate or related agents may have a potential role as adjunctive therapy in patients with diabetes mellitus.

Adult↗

Differential regulation of counterregulatory hormone secretion and symptoms during hypoglycemia in IDDM. Effect of glycemic control.

OBJECTIVE: To determine 1) if there was a differential effect of glycemic control on individual counterregulatory hormone responses to hypoglycemia in patients with insulin-dependent diabetes mellitus (IDDM), 2) whether these modifications affect hypoglycemic symptom perception, and 3) if there was a level of glycemic control below which counterregulatory and symptomatic responses to hypoglycemia become consistently altered. RESEARCH DESIGN AND METHODS: We performed hypoglycemic clamp studies on 38 patients with IDDM and 38 healthy control subjects. Glucose was lowered from 5.0 to 2.2 mmol/l over 3 h in decrements of 0.6 mmol/l each 30 min. Epinephrine, cortisol, growth hormone (GH), glucagon, and symptom score were measured at each glucose plateau. RESULTS: In IDDM patients, HbA1 levels were positively correlated with incremental epinephrine (r = 0.58, P < 0.001) and cortisol (r = 0.52, P < 0.01) responses, but inversely correlated with GH responses (r = -0.31, P < 0.05). The increase in symptom score correlated with the epinephrine response in the IDDM patients (r = 0.57, P < 0.001), but not in the healthy control subjects (r = -0.02, NS). In IDDM patients with HbA1 < or = 7.8% (n = 7), the epinephrine, cortisol, and symptomatic responses to hypoglycemia were blunted, but GH secretion was preserved. CONCLUSIONS: These data suggest that 1) there is differential regulation of counterregulatory hormone secretion that is dependent on the level of glycemic control, 2) epinephrine is an important determinant of symptom perception in IDDM patients, but not in healthy control subjects, and 3) multiple defects in counterregulatory hormone secretion and symptom perception are consistently observed in patients with HbA1 levels < or = 7.8%.

Adult↗

Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man.

Two study protocols to examine the effects of chronic (72-96 h) physiologic euglycaemic hyperinsulinaemia (+ 72 pmol/l) and chronic hyperglycaemic (+ 1.4 mmol/l) hyperinsulinaemia (+ 78 pmol/l) on insulin sensitivity and insulin secretion were performed in 15 healthy young subjects. Subjects received a three-step euglycaemic insulin (insulin infusion rates = 1.5, 3, and 6 nmol.kg-1.min-1) clamp and a hyperglycaemia (6.9 mmol/l) clamp before and after chronic insulin or glucose infusion. Following 4 days of sustained euglycaemic hyperinsulinaemia whole body glucose disposal decreased by 20-40%. During each insulin clamp step, the defect in insulin action was accounted for by impaired non-oxidative glucose disposal (p < 0.01). Chronic euglycaemic hyperinsulinaemia did not alter insulin-mediated suppression of hepatic glucose production. Following insulin infusion the ability of hyperglycaemia to stimulate insulin secretion was significantly diminished. Following 72 h of chronic glucose infusion (combined hyperglycaemic hyperinsulinaemia), there was no change in whole body glucose disposal. However, glucose oxidation during each insulin clamp step was significantly increased and there was a reciprocal decline in non-oxidative glucose disposal by 25-39% (p < 0.01); suppression of hepatic glucose production by insulin was unaltered by chronic hyperglycaemic hyperinsulinaemia. Chronic glucose infusion increased the plasma insulin response to acute hyperglycaemia more than twofold. These results demonstrate that chronic, physiologic hyperinsulinaemia, whether created by exogenous insulin infusion or by stimulation of endogenous insulin secretion, leads to the development of insulin resistance, which is characterized by a specific defect in the non-oxidative (glycogen synthetic) pathway. These findings indicate that hyperinsulinaemia should be considered, not only as a compensatory response to insulin resistance, but also as a self-perpetuating cause of the defect in insulin action.

Adult↗

Free fatty acid and glucose metabolism in human aging: evidence for operation of the Randle cycle.

We assessed insulin effects on plasma free fatty acid (FFA) and glucose metabolism in seven elderly (71 +/- 2 yr) and in seven younger (21 +/- 1 yr) subjects matched for body weight and body mass index but not for percent body fat (32.4 +/- 3.8% in elderly vs. 20.4 +/- 3.5% in young, P < 0.05), by performing sequential euglycemic clamps at five insulin doses (0.6, 1.5, 3, 6, and 15 pmol.min-1.kg-1) in combination with indirect calorimetry and [1-14C]palmitate plus [3-3H]glucose infusion. At baseline, plasma FFA concentration, turnover infusion. At baseline, plasma FFA concentration, turnover and oxidation, and total lipid oxidation were all increased in the elderly (897 +/- 107 vs. 412 +/- 50 mumol/l and 11.2 +/- 1.4 vs. 5.14 +/- 0.86, 3.45 +/- 0.65 vs. 1.37 +/- 0.25, and 4.63 +/- 0.72 vs. 3.01 +/- 0.33 mumol.min-1.kg-1 lean body mass, P < 0.05 for all comparisons), whereas glucose turnover was similar as a result of decreased glucose oxidation (8.2 +/- 1.4 vs. 13 +/- 1.9 mumol.min-1.kg-1 lean body mass, P < 0.05) and increased glucose storage (6.6 +/- 1.4 vs. 1.7 +/- 1.3 mmol.min-1.kg-1 lean body mass, P < 0.05). At all insulin infusions, plasma FFA concentration, turnover and oxidation, and total lipid oxidation were higher in the elderly than in the younger group (P < 0.05). However, if normalized per fat mass, all FFA and lipid metabolic fluxes, both in the postabsorptive state and during hyperinsulinemia, were comparable in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Relation of pressor responsiveness to angiotensin II and insulin resistance in hypertension.

To test the hypothesis that the hypertension associated with insulin resistance is secondary to an altered responsiveness of the vasculature to pressor agents, we evaluated the relationship between insulin resistance and pressor responses to angiotensin II (AII) in 21 hypertensive (HT) and 8 normotensive (NT) subjects on both a high (200 meq) and a low (10 meq) sodium diet. When sodium balance was achieved, each supine fasting subject underwent an AII infusion at a rate of 3 ng/kg per min for 60 min, with blood pressure monitored every 2 min. On the next day under similar conditions, a euglycemic hyperinsulinemic clamp was performed, with plasma glucose clamped at 90 mg/dl for 120 min. There was no significant relationship between the glucose disposal rate (M) or the insulin sensitivity index (M divided by the mean insulin level [M/I]) and blood pressure response to AII in the NTs, but a highly significant (P < 0.019) negative correlation (r = -0.55) in the HTs. Furthermore, in eight lean HTs whose body mass index was identical to that observed in the NTs, the relationship was even more striking (P < 0.008; r = -0.85). The results on high and low salt diets were similar; however, the M and M/I were significantly increased (P < 0.05) in the NTs but not HTs with sodium restriction. In conclusion, HTs but not NTs display a striking correlation between pressor response to AII and insulin resistance. This relationship is independent of the level of sodium intake. Furthermore, sodium intake modifies insulin sensitivity in NTs but not HTs. These results strongly suggest that a primary change in pressor response to vasoactive agents in insulin-resistant subjects can contribute to their elevated blood pressure.

Adult↗

Stimulus specificity of defects in counterregulatory hormone secretion in insulin-dependent diabetes mellitus: effect of glycemic control.

Counterregulatory hormone responses to hypoglycemia are impaired in subjects with insulin-dependent diabetes mellitus (IDDM) in strict glycemic control. To determine whether these defects are specific for hypoglycemia, we examined counterregulatory hormone responses during a 3-h hypoglycemic hyperinsulinemic clamp (14.4 pmol/kg.min) that lowered plasma glucose from 5.0 to 2.2 mmol/L in 9 well controlled IDDM patients (hemoglobin-A1, 7.5 +/- 0.8%), 9 poorly controlled patients (hemoglobin-A1, 12.5 +/- 1.5%), and 10 healthy volunteers. Counterregulatory hormone secretion was compared with responses to non-glucose secretagogues for epinephrine and norepinephrine (cold pressor test), ACTH (overnight metyrapone test), and GH (L-arginine infusion). During hypoglycemia, epinephrine and cortisol responses were lower in the IDDM group in strict glycemic control than those in the poorly controlled IDDM group or healthy volunteers (P < 0.05). In response to the cold pressor test, the areas under the curve for epinephrine and norepinephrine were also reduced in the well controlled IDDM group (P < 0.05 vs. healthy volunteers). The ACTH response to hypoglycemia was not significantly reduced in the well controlled IDDM, whereas the response to metyrapone was actually greater in this group (P < 0.05 vs. poorly controlled IDDM). GH responses to both hypoglycemia and arginine were highest in the well controlled diabetic patients. These data suggest that 1) the reduced epinephrine responses in well controlled IDDM may not be specific for the hypoglycemic stimulus alone, but may also occur in response to other nonhypoglycemic stimuli; 2) cortisol responses to hypoglycemia are reduced in well controlled IDDM, whereas the ACTH response to a non-hypoglycemic stimulus remains intact; and 3) GH responses to both hypoglycemic and nonhypoglycemic stimuli are preserved in well controlled IDDM. The preservation of ACTH and GH responses to metyrapone and arginine, respectively, suggests adequate pituitary functional reserve in IDDM patients in strict glycemic control in response to nonhypoglycemic stimuli.

Adolescent↗

Insulin modulates circulating endothelin-1 levels in humans.

Recent data indicate that insulin stimulates synthesis of the vasoconstrictor peptide endothelin-1 (ET-1) by cultured vascular endothelial cells in vitro. To determine whether insulin modulates ET levels in vivo and whether this effect is important in the pathogenesis of obesity-associated hypertension, we measured circulating immunoreactive ET-1 levels during euglycemic hyperinsulinemic clamps (20 mU/m2.min-1 for 120 minutes) in eight obese women (body mass index, 36 +/- 1 kg/m2) before and after 10 weeks on an 800-kcal/d protein-sparing liquid diet. During the clamp that preceded weight loss, insulin levels were increased from 17 +/- 2 to 51 +/- 3 mU/L and this was associated with an increment in ET-1 level from 28 +/- 3 to 33 +/- 3 pg/mL (P < .05). After weight loss, insulin levels were increased from 10 +/- 2 to 47 +/- 3 mU/L during the clamp, and there was a corresponding increase in ET-1 levels from 24 +/- 3 to 30 +/- 3 pg/mL (P < .025). The reduction in basal ET-1 level (from 28 +/- 3 to 24 +/- 3 pg/mL) with weight loss correlated strongly with the reduction in fasting immunoreactive insulin level (from 17 +/- 2 to 10 +/- 2 mU/L; r = .92, P < .01). The decrease in blood pressure with weight loss (from 130 +/- 6/73 +/- 3 to 118 +/- 4/72 +/- 3 mm Hg) did not correlate with the corresponding reduction in circulating ET-1 levels. These results indicate that insulin modulates ET-1 levels in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Effect of sodium intake on insulin sensitivity.

To examine the effects of sodium intake on insulin sensitivity, we performed euglycemic insulin clamp studies (40 mU.m-2.min-1) in eight healthy normotensive nondiabetic white males (age = 36 +/- 5 yr; wt = 66 +/- 3 kg) after 5 days on high (200 meq/day)- and low (10 meq/day)-sodium diets administered in random order. High sodium intake was associated with significantly greater urinary sodium excretion (160 +/- 7 vs. 8 +/- 2 meq/day; P < 0.0001), suppression of plasma aldosterone (7 +/- 3 vs. 38 +/- 6 ng/dl; P < 0.001) and renin (1.5 +/- 0.2 vs. 6.0 +/- 0.9 ng.ml-1.h-1; P < 0.005) levels, but no change in blood pressure (116 +/- 3/63 +/- 2 vs. 114 +/- 3/64 +/- 2 mmHg; P = not significant). The rate of glucose infusion during the clamp was significantly reduced during the high- vs. low-sodium diet (279 +/- 19 vs. 334 +/- 24 mg.m-2.min-1; P < 0.01). This impairment in insulin sensitivity was not related to changes in serum potassium, epinephrine, norepinephrine, cortisol, or growth hormone but was highly correlated with an increment in circulating free fatty acid levels during high sodium intake (r = 0.82, P < 0.05). These data suggest that 1) high sodium intake may exacerbate insulin resistance by increasing circulating free fatty acids, and 2) differences in sodium intake may influence measures of insulin sensitivity in other disease states.

Adult↗

Disparate effects of weight loss on insulin sensitivity and erythrocyte sodium-lithium countertransport activity.

Previous investigations have demonstrated an association between impaired insulin sensitivity and elevated erythrocyte sodium-lithium countertransport (Na(+)-Li+ CT) activity. It has been speculated that insulin resistance and endogenous hyperinsulinemia are causally related to the development of elevated Na(+)-Li+ CT activity. To test this hypothesis, we measured insulin sensitivity (euglycemic insulin clamp technique) and Na(+)-Li+ CT activity in eight obese women before (weight = 102 +/- 5 kg) and after (weight = 88 +/- 5 kg; P < .001) a 10 week weight reduction program. Maximal velocity of Na(+)-Li+ CT activity did not change (0.50 +/- 0.09 v 0.49 +/- 0.10 mmol/L red blood cells/h; P = NS) despite the significant improvement in insulin sensitivity (73 +/- 12 vs 110 +/- 7 mg/m2/min; P < .0025) and reduction in fasting insulin levels (17 +/- 2 v 10 +/- 2 microU/mL; P < .05) that accompanied weight loss. These results suggest that insulin resistance and hyperinsulinemia are not linked pathophysiologically to the development of elevated Na(+)-Li+ CT activity.

Adult↗

Effect of insulin on oxidative and nonoxidative pathways of free fatty acid metabolism in human obesity.

The dose-response relationship between the plasma insulin concentration and oxidative and nonoxidative pathways of free fatty acid (FFA) metabolism was examined in 11 obese and 7 lean subjects using a stepwise insulin clamp technique in combination with indirect calorimetry and infusion of [1-14C]palmitate. The fasting plasma FFA concentration was elevated in obese subjects (793 +/- 43 vs. 642 +/- 39 mumol/l; P less than 0.01) and was associated with an increased basal rate of plasma FFA turnover, FFA oxidation, and nonoxidative FFA disposal, i.e., reesterification (all P less than 0.01). Suppression of plasma FFA turnover by physiological increments in plasma insulin was impaired in obese compared with lean subjects. However, plasma FFA turnover expressed per kilogram fat mass was normally suppressed by insulin in obese subjects. Although insulin suppressed plasma FFA oxidation to the same extent in lean and obese subjects, inhibition of total lipid oxidation by insulin was impaired in the obese group. Obese subjects had an enhanced basal rate of nonoxidative FFA disposal, which was suppressed less by physiological increments in plasma insulin compared with lean controls. Therefore, we conclude that 1) lipolysis in uncomplicated obesity is normally sensitive to insulin; the enhanced FFA flux is simply a consequence of the increased fat mass. 2) Nonoxidative FFA disposal expressed per lean body mass is enhanced in obese subjects and correlates with the increase in plasma FFA concentration and fat mass. 3) Enhanced oxidation of intracellular lipids contributes to the enhanced rate of total lipid oxidation in obese subjects.

Fatty Acids, Nonesterified↗

Effect of glycemic control on the overnight dexamethasone suppression test in patients with diabetes mellitus.

Because many of the clinical features associated with Cushing's syndrome are frequently found in patients with diabetes mellitus, diabetic patients are often evaluated for Cushing's syndrome. The initial test for Cushing's syndrome is the 1 mg overnight dexamethasone suppression test (DST), but its value as a screening test in diabetic subjects, especially those with poor glycemic control, has been questioned. To address this issue, an overnight DST was administered to 100 subjects with diabetes. Only 7 patients failed to suppress their plasma cortisol to less than 140 nmol/L (5.0 micrograms/dL), achieving a specificity of 93%. There was no relation between acute glycemic control (as measured by the mean of 4 serum glucose values obtained before receiving dexamethasone) or chronic glycemic control (as measured by glycohemoglobin) and false positive responses to the 1 mg overnight DST. The mean of the measures of acute glycemic control of the 7 subjects who had false positive results, 14.4 +/- 2.8 mmol/L, was not significantly different than that of the 93 subjects with normal responses, 13.2 +/- 3.3 mmol/L. Similarly, the mean glycohemoglobin of the subjects with false positive results, 12.8 +/- 2.4%, was not significantly different than that of the subjects with normal responses, 12.9 +/- 2.5%. There was no correlation between plasma cortisol after dexamethasone and glycohemoglobin (r = 0.05), and only a weak correlation with the mean serum glucose (r = 0.21). We conclude that the 1 mg overnight DST is a valid screening test for Cushing's syndrome in patients with diabetes, regardless of glycemic control.

Adult↗

Intermittent hypoglycemia impairs glucose counterregulation.

IDDM patients who maintain strict glycemic control have impaired counterregulatory hormone and symptomatic responses to hypoglycemia. To test the hypothesis that intermittent exposure to hypoglycemia plays an etiological role in these defective responses, we produced 4 consecutive daily episodes of hypoglycemia in 10 healthy, nondiabetic volunteers by using the insulin clamp technique. Fasting (5.3 +/- 0.1 vs. 5.4 +/- 0.1 mM) and nadir (2.3 +/- 0.1 vs. 2.4 +/- 0.1 mM) glucose levels achieved during insulin infusion did not differ on study days 1 and 4. In contrast, the glucose levels required to stimulate an increase in EPI (2.8 vs. 3.1 mM), glucagon (2.8 vs. 3.2 mM), cortisol (2.4 vs. 2.9 mM), GH (2.6 vs. 3.0 mM), and autonomic hypoglycemic symptoms (2.2 vs. 2.5 mM) were all significantly lower on study day 4 versus study day 1 (P < 0.005-0.05). Basal levels of EPI and cortisol, but not glucagon, GH, or NE also were reduced on the final study day. We conclude that intermittent hypoglycemia can result in attenuation of the hormonal and symptomatic responses to insulin-induced hypoglycemia and may contribute to the defective counterregulatory responses in patients with well-controlled IDDM.

Adult↗

Alterations in glucose metabolism during menstrual cycle in women with IDDM.

OBJECTIVE: To examine the hormonal mechanisms underlying the variability in glycemic control during the different phases of the menstrual cycle in women with insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: Hyperglycemic (11.7 +/- 0.1 mM), hyperinsulinemic (24 +/- 3 mU/L) clamp studies were performed in 16 women with IDDM during the follicular (day 8 +/- 1) and luteal (day 23 +/- 1) phases of the menstrual cycle. Seven of the patients (group 1) experienced worsening glucose control during the luteal phase, whereas nine patients (group 2) did not. RESULTS: In group 1, glucose metabolism fell from 30.2 +/- 3.8 mumol.kg-1.min-1 during the follicular phase to 24.5 +/- 2.0 mumol.kg-1.min-1 during the luteal phase (P = 0.09), whereas in group 2 it increased from 18.5 +/- 1.2 to 23.2 +/- 2.3 mumol.kg-1.min-1 (P = 0.03). The decrease in glucose metabolism during the luteal phase in patients in group 1 was associated with a significant rise in the serum estradiol levels from the follicular to luteal phase (164 +/- 39 vs. 352 +/- 59 pM, P = 0.006), whereas this rise was not observed in group 2 (334 +/- 156 vs. 423 +/- 74 pM, NS). Changes in other reproductive hormones (progesterone, testosterone, dihydrotestosterone, androstenedione, luteinizing hormone, follicular-stimulating hormone, or prolactin) were not related to the differences in glucose uptake in the two groups. CONCLUSIONS: 1) Marked heterogeneity in glucose metabolism is seen throughout the menstrual cycle in women with IDDM, 2) a subgroup of patients exhibits worsening premenstrual hyperglycemia and a decline in insulin sensitivity during the luteal phase, and 3) the deterioration in glucose uptake in this subgroup was associated with a greater increment in estradiol levels from the follicular to the luteal phase.

Adult↗

Effect of sulphonylurea on glucose-stimulated insulin secretion in healthy and non-insulin dependent diabetic subjects: a dose-response study.

The effect of a rapid-acting sulphonylurea, glipizide, on the dose-response relationship between the beta-cell response (insulin and C-peptide secretion) and the ambient plasma glucose concentration was examined in 12 healthy and 6 non-insulin-dependent diabetic subjects. The subjects participated in two sets of experiments which were performed in random order: (A) four hyperglycaemic clamp studies, during which the plasma glucose concentration was raised for 120 min by 1 (only in healthy subjects), 3, 7, and 17 mmol/l; and (B) the same four hyperglycaemic clamp studies preceded by ingestion of 5 mg glipizide. All subjects participated in a further study, in which glipizide was ingested and the plasma glucose concentration was maintained at the basal level. In control subjects in the absence of glipizide, the first-phase plasma insulin response (0-10 min) increased progressively with increasing plasma glucose concentration up to 10 mmol/l, above which it tended to plateau. Glipizide augmented the first-phase insulin response without changing the slope of the regression line relating plasma insulin to glucose concentrations. The second-phase plasma insulin response (20-120 min) increased linearly with increasing hyperglycaemia (r = 0.997). Glipizide alone increased the plasma insulin response by 180 pmol/l. A similar increase in plasma insulin response following glipizide was observed at each hyperglycaemic step, indicating that glipizide did not affect the sensitivity of the beta-cell to glucose. First-phase insulin secretion was reduced in the type 2 (non-insulin-dependent) diabetic patients, and was not influenced by glipizide.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects.

The effect of metformin on glucose metabolism was examined in eight obese (percent ideal body weight, 151 +/- 9%) and six lean (percent ideal body weight, 104 +/- 4%) noninsulin-dependent diabetic (NIDD) subjects before and after 3 months of metformin treatment (2.5 g/day). Fasting plasma glucose (11.5-8.8 mmol/L), hemoglobin-A1c (9.8-7.7%), oral glucose tolerance test response (20.0-17.0 mmol/L; peak glucose), total cholesterol (5.67-4.71 mmol/L), and triglycerides (2.77-1.52 mmol/L) uniformly decreased (P less than 0.05-0.001) after metformin treatment; fasting plasma lactate increased slightly from baseline (1.4 to 1.7 mmol/L; P = NS). Body weight decreased by 5 kg in obese NIDD subjects, but remained constant in lean NIDD. Basal hepatic glucose production declined in all diabetics from 83 to 61 mg/m2.min (P less than 0.01), and the decrease correlated (r = 0.80; P less than 0.01) closely with the fall in fasting glucose concentration. Fasting insulin (115 to 79 pmol/L) declined (P less than 0.05) after metformin. During a 6.9 mmol/L hyperglycemic clamp, glucose uptake increased in every NIDD subject (113 +/- 15 to 141 +/- 12 mg/m2.min; P less than 0.001) without a change in the plasma insulin response. During a euglycemic insulin clamp, total glucose uptake rose in obese NIDD subjects (121 +/- 10 to 146 +/- 9 mmol/m2.min; P less than 0.05), but decreased slightly in lean NIDD (121 +/- 10 to 146 +/- 0.5; P = NS). Hepatic glucose production was suppressed by more than 80-90% in all insulin clamp studies before and after metformin treatment. In conclusion, metformin lowers the fasting plasma glucose and insulin concentrations, improves oral glucose tolerance, and decreases plasma lipid levels independent of changes in body weight. The improvement in fasting glucose results from a reduction in basal hepatic glucose production. Metformin per se does not enhance tissue sensitivity to insulin in NIDD subjects. The improvement in glucose metabolism under hyperglycemic, but not euglycemic, conditions suggests that metformin augments glucose-mediated glucose uptake. Metformin has no stimulatory effect on insulin secretion.

Blood Glucose↗

Effects of glyburide on in vivo insulin-mediated glucose disposal.

The purpose of this study was to examine the effects of glyburide on peripheral (muscle) and hepatic insulin sensitivity in patients with non-insulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes mellitus (IDDM) as well as in healthy control subjects. In protocol 1, 10 patients with NIDDM and seven young healthy control subjects were studied. Changes in insulin sensitivity (40 mU/m2.min euglycemic insulin clamp), hepatic glucose production (3-[3H]glucose turnover), and insulin secretion (+125 mg/dL hyperglycemic clamp) were measured before and after 3 months (in patients with NIDDM) and 6 weeks (in young control subjects) of glyburide therapy. In protocol 2, five patients with IDDM and eight patients with insulin-treated NIDDM were evaluated before and after two months of glyburide therapy (20 mg per day). Changes in daily insulin requirements, 24-hour plasma glucose profiles, glycohemoglobin, glucagon-stimulated C-peptide secretion, insulin sensitivity, and hepatic glucose production were measured. In protocol 1, glyburide significantly improved insulin sensitivity (p less than 0.01) and insulin secretion (p less than 0.01) in the NIDDM patients. The elevated rates of hepatic glucose production (2.4 +/- 0.3 mg/kg.min) were reduced after glyburide therapy (1.7 +/- 0.2 mg/kg.min; p less than 0.01) and were highly correlated with an improvement in fasted plasma glucose levels (r = 0.92; p less than 0.001). Insulin sensitivity also improved in the young healthy control subjects after glyburide therapy (6.5 +/- 0.5 to 7.6 +/- 0.7 mg/kg.min; p less than 0.05). In protocol 2, glyburide treatment produced no change in daily insulin requirement (54 +/- 8 versus 53 +/- 7 units per day), mean 24-hour glucose levels (177 +/- 20 versus 174 +/- 29 mg/dL), glycohemoglobin (10.1 +/- 1.0 percent versus 9.5 +/- 7 percent), C-peptide secretion, insulin sensitivity, or basal hepatic glucose production (p values not significant) in the IDDM patients. In contrast, the insulin-treated NIDDM patients had significant reductions in mean daily insulin requirement (72 +/- 6 versus 58 +/- 9 units per day; p = 0.05), mean 24-hour plasma glucose levels (153 +/- 10 to 131 +/- 5 mg/dL; p less than 0.05), and glycohemoglobin levels (10.3 +/- 0.7 percent to 8.0 +/- 0.4 percent; p less than 0.05) and an improvement in C-peptide secretion (0.24 +/- 0.07 to 0.44 +/- 0.09 pmol/mL; p = 0.08). Stimulated C-peptide levels were highly correlated with a reduction in insulin dose observed during the 2-month treatment period (r = 0.93; p less than 0.001). Insulin sensitivity improved slightly but not significantly after glyburide treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗