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OBJECTIVE—To examine the effect of aging on insulin secretion (first- and second-phase insulin release) and insulin sensitivity in people with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS—First- and second-phase insulin secretion and insulin sensitivity were assessed in hyperglycemic clamp experiments in 266 individuals with NGT and 130 individuals with IGT, ranging in age from ∼20 to ∼70 years. Changes in β-cell function were compared using the disposition index to adjust for differences in insulin sensitivity. RESULTS—As expected, both phases of insulin release and insulin sensitivity were reduced in individuals with IGT (all P < 0.01). Insulin sensitivity was not independently correlated with age in either group. In people with NGT, the disposition index for first- and second-phase insulin release decreased similarly at a rate of ∼0.7% per year. In people with IGT, the disposition indexes for first- and second-phase insulin release decreased at greater rates (∼2.2 and 1.4% per year, P = 0.002 and 0.009, respectively, vs. NGT), with the decrease in first phase being greater than that of second phase (P = 0.025). CONCLUSIONS—Insulin secretion (both first and second phase) normally decreases at a rate of ∼0.7% per year with aging; this decrease in β-cell function is accelerated about two-fold in people with impaired glucose tolerance—first phase to a greater extent than second phase. Finally, aging per se has no effect on insulin sensitivity independent of changes in body composition.

Severe hypoglycemia, the most serious side effect of sulfonylurea therapy, has been reported to occur more frequently with glyburide than glimepiride. The present studies were undertaken to test the hypothesis that a differential effect on glucagon secretion may be involved. We performed hyperinsulinemic hypoglycemic (approximately 2.5 mmol/L) clamps in 16 healthy volunteers who received in randomized order placebo, glyburide (10 mg), and glimepiride (4 mg) just before beginning the insulin infusion and measured plasma glucagon, insulin, C-peptide, glucagon, epinephrine, cortisol, and growth hormone levels during the clamp and during a 3-hour recovery period after discontinuation of the insulin infusion. Neither sulfonylurea altered glucagon responses or those of other counterregulatory hormones (except cortisol) during the clamp. However, glyburide delayed plasma glucose recovery from hypoglycemia (plasma glucose at end of recovery period: control, 4.9 +/- 0.2 mmol/L; glyburide, 3.7 +/- 0.2 mmol/L; P = .0001; glimepiride, 4.5 +/- 0.2 mmol/L; P = .08). Despite lower plasma glucose levels, glyburide stimulated insulin secretion during this period (0.89 +/- 0.13 vs 1.47 +/- 0.15 pmol x kg(-1) x min(-1), control vs glyburide; P = .001), whereas glimepiride did not (P = .08). Short-term administration of glyburide or glimepiride did not alter glucagon responses during hypoglycemia. In contrast, during recovery from hypoglycemia, glyburide but not glimepiride inappropriately stimulates insulin secretion at low plasma glucose levels. This differential effect on insulin secretion may be an important factor in explaining why glyburide causes severe hypoglycemia more frequently than glimepiride.

OBJECTIVE—In advanced β-cell failure, counterregulatory glucagon responses may be impaired due to a reduced decrement in insulin secretion during the development of hypoglycemia. The present studies were therefore undertaken to test the hypothesis that these may be improved by increasing this decrement in insulin secretion. RESEARCH DESIGN AND METHODS—Twelve subjects with type 2 diabetes who have been insulin requiring were studied as a model of advanced β-cell failure. Glucagon responses were examined during a 90-min hypoglycemic clamp (∼2.8 mmol/l) on two separate occasions. On one occasion, tolbutamide was infused for 2 h before the clamp so that the decrement in insulin secretion during the induction of hypoglycemia would be increased. On the other occasion, normal saline was infused as a control. RESULTS—Before the hypoglycemic clamp, infusion of tolbutamide increased insulin secretion ∼1.9-fold (P < 0.001). However, during hypoglycemia, insulin secretion decreased to similar rates on both occasions (P = 0.31) so that its decrement was approximately twofold greater following the tolbutamide infusion (1.63 ± 0.20 vs. 0.81 ± 0.17 pmol · kg−1 · min−1, P < 0.001). This was associated with more than twofold-greater glucagon responses (42 ± 11 vs. 19 ± 8 ng/l, P < 0.002) during the hypoglycemic clamp but unaltered glucagon responses to intravenous arginine immediately thereafter (449 ± 50 vs. 453 ± 50 ng/l, P = 0.78). CONCLUSIONS—Increasing the decrement in insulin secretion during the development of hypoglycemia improves counterregulatory glucagon responses in advanced β-cell failure. These findings further support the concept that the impaired counterregulatory glucagon responses in advanced β-cell failure may at least partially be due to a reduced decrement in insulin secretion.

OBJECTIVE—Animal and in vitro studies indicate that a decrease in β-cell insulin secretion, and thus a decrease in tonic α-cell inhibition by intraislet insulin, may be an important factor for the increase in glucagon secretion during hypoglycemia. However, in humans this role of decreased intraislet insulin is still unclear. RESEARCH DESIGN AND METHODS—We studied glucagon responses to hypoglycemia in 14 nondiabetic subjects on two separate occasions. On both occasions, insulin was infused from 0 to 120 min to induce hypoglycemia. On one occasion, somatostatin was infused from −60 to 60 min to suppress insulin secretion, so that the decrement in intraislet insulin during the final 60 min of hypoglycemia would be reduced. On the other occasion, subjects received an infusion of normal saline instead of the somatostatin. RESULTS—During the 2nd h of the insulin infusion, when somatostatin or saline was no longer being infused, plasma glucose (∼2.6 mmol/l) and insulin levels (∼570 pmol/l) were comparable in both sets of experiments (both P > 0.4). In the saline experiments, insulin secretion remained unchanged from baseline (−90 to −60 min) before insulin infusion and decreased from 1.20 ± 0.12 to 0.16 ± 0.04 pmol · kg−1 · min−1 during insulin infusion (P < 0.001). However, in the somatostatin experiments, insulin secretion decreased from 1.18 ± 0.12 pmol · kg−1 · min−1 at baseline to 0.25 ± 0.09 pmol · kg−1 · min−1 before insulin infusion so that it did not decrease further during insulin infusion (−0.12 ± 0.10 pmol · kg−1 · min−1, P = 0.26) indicating the complete lack of a decrement in intraislet insulin during hypoglycemia. This was associated with ∼30% lower plasma glucagon concentrations (109 ± 7 vs. 136 ± 9 pg/ml, P < 0.006) and increments in plasma glucagon above baseline (41 ± 8 vs. 67 ± 11 pg/ml, P < 0.008) during the last 15 min of the hypoglycemic clamp. In contrast, increases in plasma growth hormone were ∼70% greater during hypoglycemia after somatostatin infusion (P < 0.007), suggesting that to some extent the increases in plasma glucagon might have reflected a rebound in glucagon secretion. CONCLUSIONS—These results provide direct support for the intraislet insulin hypothesis in humans. However, the exact extent to which a decrement in intraislet insulin accounts for the glucagon responses to hypoglycemia remains to be established.

Insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) are required for cell proliferation in vitro, raising the possibility that an autocrine IGF-1-IGF-1R system may be present in vivo and become activated in the viable ventricular myocytes shortly after infarction. Therefore, following the in vivo documentation of left ventricular failure in rats subjected to occlusion of the left coronary artery, the unaffected myocytes of the left ventricle were enzymatically dissociated and the expression of IGF-1R and IGF-1 mRNAs were measured at 12 h and at 1, 2-3, and 7 days after surgery. The level of expression of IGF-1R mRNA increased at 12 h and remained elevated at 1 and 2-3 days following coronary ligation. In addition, an increased level of IGF-1R protein on these cells was found. This phenomenon was coupled with the enhanced expression of IGF-1 mRNA in the muscle cells at all intervals. Myocardial infarction was also accompanied by an upregulation of proliferating cell nuclear antigen (PCNA) mRNA in myocytes and the detection of PCNA protein in nearly 1% of the cells. Similarly, bromodeoxyuridine labeling demonstrated that a comparable number of myocytes was positively stained. Finally, mitotic images in myocytes were observed. Thus, the IGF-1R-IGF-1 autocrine system may modulate myocyte cellular hyperplasia in the failing heart.

To determine whether cardiac failure produced by chronic coronary artery stenosis was associated with the activation of myocyte cellular hyperplasia in the myocardium, the changes in number and size of left ventricular myocytes were measured in rats 3 months after surgery. The hypertrophied left ventricle was found to possess 44%, 32%, 49%, and 48% fewer mononucleated, binucleated, trinucleated, and tetranucleated myocytes, respectively. In contrast, the hypertrophied right ventricle contained 1.49 x 10(6) more myocytes as a result of a 2.1-fold, 1.4-fold, and 1.4-fold increase in mononucleated, binucleated, and tetranucleated myocytes. Myocyte cell volume was seen to increase 49% and 21% in left and right ventricular myocytes, respectively. The process of myocyte cellular hyperplasia in the right ventricular myocardium was accompanied by capillary proliferation, and these events were responsible for the parallel addition of newly formed cells and capillaries within the wall and mural thickening. Moreover, the in-series insertion of new myocytes contributed to right ventricular dilatation after coronary artery stenosis. In view of the fact that extensive myocardial damage and cell loss may have masked the phenomenon of myocyte cellular hyperplasia in the left ventricle, the presence of DNA synthesis in myocyte nuclei was evaluated at 3 days, 1 week, 2 weeks, 1 month, and 3 months after coronary artery stenosis. Bromodeoxyuridine (BrdU) labeling markedly increased in myocyte nuclei of both ventricles, reaching its peak at 1 and 2 weeks. BrdU labeling of nonmyocyte nuclei also increased but mostly at 2 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Made available in DSpace on 2022-04-28T18:56:02Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-05-01 To assess whether an increased genetic predisposition for type 2 diabetes mellitus (T2DM) influences the contributions of insulin resistance and impaired insulin secretion to impaired glucose tolerance (IGT), 437 subjects not known to have T2DM underwent an oral glucose tolerance test and a 3-hour hyperglycemic clamp. Plasma insulin responses and insulin sensitivity were compared between all subjects (unselected for demographic or anthropometric characteristics) who had normal glucose homeostasis and no first-degree T2DM relative (n = 133), IGT with a first-degree T2DM relative (IGT/FH+, n = 74), or IGT without a first-degree T2DM relative (IGT/FH-, n = 50). Compared with those with normal glucose homeostasis, first- and second-phase plasma insulin responses were reduced approximately 45% and 30%, respectively (both P < .001), in IGT/FH+, whereas insulin sensitivity was only approximately 20% reduced (P = .011). In contrast, in IGT/FH-, first-phase plasma insulin responses were only approximately 20% reduced (P = .016), second-phase plasma insulin responses were not reduced, but insulin sensitivity was approximately 40% reduced (P < .001). The IGT/FH+ group differed significantly from the IGT/FH- group by having 25% to 30% lower first-phase plasma insulin responses (P = .026) and 25% to 30% greater insulin sensitivity (P = .027). Adjustment for obesity abolished the differences in insulin resistance but not plasma insulin responses. However, when the IGT groups were stratified into subgroups based on body mass index (BMI), first-phase plasma insulin responses were approximately 30% lower in IGT/FH+ with a BMI of at least 27 kg/m2 (P = .018) but similar in IGT/FH+ with a BMI less than 27 kg/m2 compared with the corresponding IGT/FH- subgroups. We conclude that, in IGT, an increased genetic predisposition for T2DM increases the contribution of impaired insulin secretion to its pathophysiology. This effect is enhanced by obesity. Department of Endocrinology Carl T Hayden VA Medical Center, Phoenix, AZ 85012 Department of Internal Medicine University Medical Center Utrecht, Utrecht Department of Clinical Medicine Faculdade de Medicina Botucatu University of Sao Paulo State, Sao Paulo Department of Internal Medicine II Ludwig-Maximilians University, Munich Diabetes/Metabolism Unit Henry Dunant Foundation, Athens Department of Medicine University of Rochester School of Medicine, Rochester, NY 14642

To examine the effect of aging on insulin secretion (first- and second-phase insulin release) and insulin sensitivity in people with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT).First- and second-phase insulin secretion and insulin sensitivity were assessed in hyperglycemic clamp experiments in 266 individuals with NGT and 130 individuals with IGT, ranging in age from approximately 20 to approximately 70 years. Changes in beta-cell function were compared using the disposition index to adjust for differences in insulin sensitivity.As expected, both phases of insulin release and insulin sensitivity were reduced in individuals with IGT (all P0.01). Insulin sensitivity was not independently correlated with age in either group. In people with NGT, the disposition index for first- and second-phase insulin release decreased similarly at a rate of approximately 0.7% per year. In people with IGT, the disposition indexes for first- and second-phase insulin release decreased at greater rates ( approximately 2.2 and 1.4% per year, P = 0.002 and 0.009, respectively, vs. NGT), with the decrease in first phase being greater than that of second phase (P = 0.025).Insulin secretion (both first and second phase) normally decreases at a rate of approximately 0.7% per year with aging; this decrease in beta-cell function is accelerated about two-fold in people with impaired glucose tolerance-first phase to a greater extent than second phase. Finally, aging per se has no effect on insulin sensitivity independent of changes in body composition.

Made available in DSpace on 2022-04-28T18:55:17Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-08-07 OBJECTIVE - To compare the pathophysiology of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) in a more comprehensive and standardized fashion than has hitherto been done. RESEARCH DESIGN AND METHODS - We studied 21 individuals with isolated IFG (IFG/normal glucose tolerance [NGT]), 61 individuals with isolated IGT (normal fasting glucose [NFG]/IGT), and 240 healthy control subjects (NFG/NGT) by hyperglycemic clamps to determine first- and second-phase insulin release and insulin sensitivity. Homeostasis model assessment (HOMA) indexes of β-cell function (HOMA-%B) and insulin resistance (HOMA-IR) were calculated from fasting plasma insulin and glucose concentrations. RESULTS - Compared with NFG/NGT, IFG/NGT had similar fasting insulin concentrations despite hyperglycemia; therefore, HOMA-IR was increased ∼30% (P < 0.05), but clampdetermined insulin sensitivity was normal (P > 0.8). HOMA-%B and first-phase insulin responses were reduced ∼35% (P < 0.002) and ∼30% (P < 0.02), respectively, but second-phase insulin responses were normal (P > 0.5). NFG/IGT had normal HOMA-IR but ∼15% decreased clamp-determined insulin sensitivity (P < 0.03). Furthermore, HOMA-%B was normal but both first-phase (P < 0.0003) and second-phase (P < 0.0001) insulin responses were reduced ∼30%. IFG/NGT differed from NFG/IGT by having ∼40% lower HOMA-%B (P < 0.012) and ∼50% greater second-phase insulin responses (P < 0.005). CONCLUSIONS - Since first-phase insulin responses were similarly reduced in IFG/NGT and NFG/IGT, we conclude that IFG is due to impaired basal insulin secretion and preferential resistance of glucose production to suppression by insulin, as reflected by fasting hyperglycemia despite normal plasma insulin concentrations and increased HOMA-IR, whereas IGT mainly results from reduced second-phase insulin release and peripheral insulin resistance, as reflected by reduced clamp-determined insulin sensitivity. © 2006 by the American Diabetes Association. Department of Endocrinology Carl T. Hayden VA Medical Center, Phoenix, AZ Department of Clinical Medicine Faculdade de Medicina Botucatu University of Sao Paulo State, Sao Paulo Department of Internal Medicine II Ludwig-Maximilians University of Munich, Munich Department of Internal Medicine University Medical Center Utrecht, Utrecht Department of Medicine University of Rochester School of Medicine, Rochester, NY Diabetes/Metabolism Unit Henry Dunant Foundation, Athens Carl T. Hayden VA Medical Center, 650 East Indian School Rd., Phoenix, AZ 85012

To assess mechanisms for postprandial hyperglycemia, we used a triple-isotope technique ([\3-3H]glucose and [14C]bicarbonate and oral [6,6-dideutero]glucose iv) and indirect calorimetry to compare components of glucose release and pathways for glucose disposal in 26 subjects with type 2 diabetes and 15 age-, weight-, and sex-matched normal volunteers after a standard meal. The results were as follows: 1) diabetic subjects had greater postprandial glucose release ( P < 0.001) because of both increased endogenous and meal-glucose release; 2) the greater endogenous glucose release ( P < 0.001) was due to increased gluconeogenesis ( P < 0.001) and glycogenolysis ( P = 0.01); 3) overall tissue glucose uptake, glycolysis, and storage were comparable in both groups ( P > 0.3); 4) glucose clearance ( P < 0.001) and oxidation ( P = 0.004) were reduced, whereas nonoxidative glycolysis was increased ( P = 0.04); and 5) net splanchnic glucose storage was reduced by ∼45% ( P = 0.008) because of increased glycogen cycling ( P = 0.03). Thus in type 2 diabetes, postprandial hyperglycemia is primarily due to increased glucose release; hyperglycemia overcomes the effects of impaired insulin secretion and sensitivity on glucose transport, but intracellular defects persist so that pathways of glucose metabolism are abnormal and glucose is shunted away from normal sites of storage (e.g., liver and muscle) into other tissues.

In type 2 diabetes mellitus (T2DM), little is known about hormonal responses to hypoglycemia. In particular, beta-cell responses to hypoglycemia have not been carefully investigated and potentially because of confounding factors or insufficient power, conflicting data have been obtained regarding growth hormone responses. We therefore compared hormonal responses including rates of insulin secretion during a 2-hour hyperinsulinemic hypoglycemic clamp in a relatively large number of nondiabetic (n=21) and moderately insulin-deficient subjects with T2DM (homeostasis model assessment of beta-cell function [HOMA-%B], 751+/-160 vs 1144+/-83 [pmol/L]/[mmol/L], P.04) (n=14) matched for age, sex, and body mass index. Subjects with T2DM were excluded for antecedent hypoglycemia, and baseline glycemia was controlled by a variable infusion of insulin overnight. Although both groups of subjects had indistinguishable plasma glucose levels at baseline and virtually identical levels of plasma insulin and glucose throughout the hypoglycemic clamp, insulin secretion decreased more slowly in the subjects with T2DM. The time required for insulin secretion to decline to half its baseline level was markedly increased (38.9+/-4.9 vs 22.3+/-1.3 minutes [SD], P.01), and insulin secretion decreased to a lesser extent (-0.79+/-0.17 vs -1.51+/-0.09 [pmol/L]/kg per minute, P.002). Moreover, responses of glucagon (28.3+/-7.3 vs 52.8+/-7.0 ng/L, P.05) and growth hormone (2.9+/-0.8 vs 6.3+/-0.9 ng/mL, P.04) were reduced in the subjects with T2DM, whereas responses of epinephrine, norepinephrine, and cortisol were similar to those in nondiabetic subjects (all P0.6). We conclude that multiple defects exist in hormonal responses to hypoglycemia in T2DM with moderate beta-cell failure. These include delayed and reduced decreases in insulin secretion, and impaired increases of plasma glucagon and growth hormone.

Type 2 diabetes mellitus (T2DM) is a heterogeneous disorder caused by a combination of genetic and acquired abnormalities that affect insulin sensitivity and insulin secretion. Currently available data suggest that insulin resistance is the acquired defect largely secondary to unhealthy lifestyles and that the major genetic factor is impaired insulin secretion. The latter is the result of both reduced beta-cell mass and functional abnormalities makes the beta-cell unable to compensate for increased insulin requirements caused by insulin resistance. Targeting both insulin resistance and impaired insulin secretion is therefore appropriate to prevent T2DM and to improve glycemic control in those with the disorder.

Made available in DSpace on 2022-04-28T18:55:37Z (GMT). No. of bitstreams: 0 Previous issue date: 2004-08-09 Background: Increased fasting plasma glucose (FPG) and 2-hour postchallenge plasma glucose (PCPG) levels with normal hemoglobin A1c (HbA 1c) levels are recognized as risk factors for cardiovascular disease. We undertook this study to determine the relationships between FPG and 2-hour PCPG levels over the normal HbA1c range and to assess the need to control FPG and 2-hour PCPG levels to achieve HbA1c targets recommended by the American Diabetes Association (ADA), International Diabetes Federation (IDF), and American College of Endocrinology (ACE). Methods: The data of all healthy individuals with HbA1c values less than 7.0% (N=457) who underwent oral glucose tolerance tests between 1986 and 2002 for either screening as potential research volunteers (93%) or diagnostic purposes (7%) were analyzed. Results: Of 404 individuals with normal HbA1c levels (

Background Rapid ventricular pacing leads to a cardiac myopathy consisting of an increase in chamber dimension, mural thinning, elevation in ventricular wall stress, and congestive heart failure, mimicking dilated cardiomyopathy in humans. However, contrasting results have been obtained concerning the mechanisms of ventricular dilation and the existence of myocardial hypertrophy. Moreover, questions have been raised regarding the occurrence of myocardial damage and cell loss in the development of the experimental myopathy. Methods and Results The functional and structural characteristics of the heart were studied in conscious dogs subjected to left ventricular pacing at 210 beats per minute for 3 weeks and 240 beats per minute for an additional week. At the time the animals were killed, measurements of myocardial structural integrity and myocyte shape, size, and number were determined by morphometric analysis of the myocardium in situ and enzymatically dissociated cells. The experimental protocol used was associated with overt cardiac failure documented by an increase in left ventricular end-diastolic pressure and a decrease in left ventricular systolic pressure and +dP/dt in combination with tachycardia, ascites, and pulmonary congestion. Although cardiac weights were not altered, cavitary diameter was increased and wall thickness was decreased from the base to the apex of the heart. Multiple foci of replacement fibrosis, comprising 6% of the myocardium, were detected across the left ventricular wall. Measurements of myocyte size and number documented a 39% loss of cells in the entire ventricle and a 61% increase in volume of the remaining viable myocytes. Myocyte hypertrophy was characterized by a 33% increase in cell length and a 23% increase in transverse area, resulting in a 23% increase in the cell length–to–cell diameter ratio. Pacing did not alter the relative proportion of mononucleated, binucleated, and multinucleated myocytes in the myocardium. Conclusions Myocyte cell loss and myocyte reactive hypertrophy are the major components of ventricular remodeling in pacing-induced dilated cardiomyopathy.