Antecedent moderate-intensity exercise has been shown to blunt autonomic, neuroendocrine, and metabolic counterregulatory responses to subsequent hypoglycemia in nondiabetic individuals. The aims of the current study were to determine 1) whether this occurs in type 1 diabetic patients and 2) whether the degree of blunting is dependent on exercise intensity. Twentyseven type 1 diabetic patients (13 women and 14 men) were studied during a single-step, 2-h hyperinsulinemic (9 pmol ⅐ kg ؊1 ⅐ min ؊1 )-hypoglycemic (ϳ2.8 mmol/l) clamp 1 day after two 90-min exercise bouts at 30% (n ‫؍‬ 11) or at 50% (n ‫؍‬ 11) VO 2max or after no prior stress (control subjects, n ‫؍‬ 25). After prior exercise at both 30 and 50% VO 2max , epinephrine (1,959 ؎ 553 and 1,528 ؎ 424 vs. 3,420 ؎ 424 pmol/l, respectively; P < 0.05) and pancreatic polypeptide (97 ؎ 32 and 98 ؎ 8 vs. 223 ؎ 32 pmol/l, respectively; P < 0.05) responses to subsequent hypoglycemia were significantly lower compared with those of control subjects. Endogenous glucose production was significantly lower, while glucose utilization and, consequently, the exogenous glucose infusion rate needed to maintain hypoglycemia were significantly greater after both exercise intensities compared with that of control subjects. Muscle sympathetic nerve activity was significantly reduced by prior exercise of both intensities at baseline (16 ؎ 4 and 22 ؎ 4 vs. 31 ؎ 3 bursts/min) and during hypoglycemia (22 ؎ 4 and 27 ؎ 5 vs. 41 ؎ 3 bursts/min) compared with that of control subjects (P < 0.05). Total hypoglycemic symptoms were also significantly lower (P < 0.05) in both exercise groups compared with the control group. In summary, repeated episodes of prolonged exercise of both low and moderate intensities blunted key autonomic (epinephrine and pancreatic polypeptide) and metabolic (endogenous glucose production and peripheral glucose uptake) counterregulatory responses to next-day hypoglycemia in type 1 diabetes. Diabetes 53: 1798 -1806, 2004 I ntensive maintenance of normal glucose levels delays or prevents the development of microvascular complications associated with diabetes (1,2). Unfortunately, an approximate threefold increase in severe hypoglycemia in these intensively treated patients (1) limits the widespread implementation of this treatment paradigm. Although excess insulin is an important contributing factor to increased hypoglycemia, with increased duration of the disease, glucagon responses to hypoglycemia in type 1 diabetes are absent (3). This leaves type 1 diabetic patients dependent on epinephrine to counter falling glucose levels. However, recent antecedent episodes of hypoglycemia have significantly reduced autonomic counterregulatory responses to subsequent hypoglycemia in nondiabetic and type 1 diabetic patients (4 -7). This has been termed hypoglycemia-associated autonomic failure (8,9) and is proposed to create a vicious cycle of hypoglycemia for the type 1 diabetic patient.Exercise has numerous therapeutic benefits. Despite this, exercise often results in hypogly...

This study tested the hypothesis that estrogen is the mechanism responsible for the sexual dimorphism present in the neuroendocrine and metabolic responses to hypoglycemia. Postmenopausal women receiving (E2; n ‫؍‬ 8) or not receiving (NO E2; n ‫؍‬ 9) estrogen replacement were compared with age-and BMI-matched male subjects (n ‫؍‬ 8) during a single-step 2-h hyperinsulinemic-hypoglycemic clamp. Plasma insulin (599 ؎ 28 pmol/l) and glucose (2.9 ؎ 0.03 mmol/l) levels were similar among all groups during the glucose clamp. In response to hypoglycemia, epinephrine (2.8 ؎ 0.6 vs. 5.8 ؎ 0.8 and 4.4 ؎ 0.5 nmol/l), glucagon (57 ؎ 8 vs. 77 ؎ 8 and 126 ؎ 18 ng/l), and endogenous glucose production (2 ؎ 2 vs. 10 ؎ 2 and 6 ؎ 3 mol ⅐ kg ؊1 ⅐ min ؊1 ) were significantly lower in E2 vs. both NO E2 and male subjects (P < 0.05). These reduced counterregulatory responses resulted in significantly greater glucose infusion rates (16 ؎ 2 vs. 6 ؎ 2 and 6 ؎ 3 mol ⅐ kg ؊1 ⅐ min ؊1 ; P < 0.01) in E2 vs. both NO E2 and male subjects. Pancreatic polypeptide was significantly lower (P < 0.05) in both the E2 and NO E2 groups compared with the male subjects (136 ؎ 20 and 136 ؎ 23 vs. 194 ؎ 16 pmol/l). Last, glycerol (36 ؎ 3 vs. 47 ؎ 5 mol/l; P < 0.05), lactate (1.4 ؎ 0.1 vs. 1.8 ؎ 0.2 mmol/l; P < 0.05), and muscle sympathetic nerve activity (19 ؎ 4 to 27 ؎ 4 vs. 27 ؎ 5 to 42 ؎ 6 bursts/min; P < 0.05) responses to hypoglycemia were all significantly lower in E2 vs. NO E2 subjects. We conclude that estrogen appears to play a major role in the sexual dimorphism present in counterregulatory responses to hypoglycemia in healthy humans. Diabetes 52:1749 -1755, 2003 M en and women respond differently to an acute bout of hypoglycemia. We have previously shown that healthy and type 1 diabetic women, compared with men, have lower catecholamine, glucagon, cortisol, growth hormone, endogenous glucose production (EGP), and lactate responses, and they have increased glycerol responses to hypoglycemia (1,2). This sexual dimorphism also appears to be present in a wide variety of physiological stresses. For example, women have been found to have reduced neuroendocrine and increased lipolytic responses to exercise (3-5) and reduced sympathetic nervous system responses to cognitive stress (6).The physiological mechanism(s) responsible for sexually dimorphic responses to stress in humans remains unknown, although it seems likely that one or more of the reproductive hormones may be responsible. Animal studies suggest that estrogen may play an important role. Estrogen administration has been shown to independently reduce catecholamine levels, either by increasing norepinephrine degradation in the brain (and thereby reducing sympathetic system drive) (7) or by decreasing secretion from the adrenal medulla (8,9). Metabolically, estrogen has been found to increase lipolysis (10), glycogen deposition (11), and glucose uptake during exercise in rats (10). Recent studies in mice even suggest that estrogen, specifically estrone sulfate, may have a direct effect on reduc...

No abstract

. Acute, sameday effects of antecedent exercise on counterregulatory responses to subsequent hypoglycemia in type 1 diabetes mellitus. Am J Physiol Endocrinol Metab 290: E1331-E1338, 2006. First published January 31, 2006 doi:10.1152/ajpendo.00283.2005.-Exercise-induced hypoglycemia can occur within hours after exercise in type 1 diabetes mellitus (T1DM) patients. This study tested the hypothesis that an acute exercise bout causes (within hours) blunted autonomic and metabolic responses to subsequent hypoglycemia in patients with T1DM. Twelve T1DM patients (3 W/9 M) were studied during a single-step, 2-h hyperinsulinemic (572 Ϯ 4 pmol/l) hypoglycemic (2.8 Ϯ 0.1 mmol/l) clamp 2 h after either a hyperinsulinemic euglycemic (AM EUG) or hypoglycemic clamp (AM HYPO) or after sitting in a chair with basal insulin infusion (AM CON) or 90 min of moderate-intensity exercise (50% V O2 max, AM EX). Both AM HYPO and AM EX significantly blunted epinephrine responses and muscle sympathetic nerve activity responses to subsequent hypoglycemia compared with both control groups. Endogenous glucose production was significantly lower and the exogenous glucose infusion rate needed to maintain the hypoglycemic level was significantly greater during subsequent hypoglycemia in AM EX vs. CON. Rate of glucose disposal (Rd) was significantly reduced following AM HYPO. In summary, within 2.5 h, both moderate-intensity AM EX and AM HYPO blunted key autonomic counterregulatory responses. Despite this, glucose Rd was reduced during afternoon hypoglycemia following morning hypoglycemia, indicating posthypoglycemic insulin resistance. After morning exercise, endogenous glucose production was blunted, but glucose Rd was maintained during afternoon hypoglycemia, thereby indicating reduced metabolic defenses against hypoglycemia. These data suggest that exercise-induced counterregulatory failure can occur very rapidly, increasing the risk for hypoglycemia in T1DM within hours. sympathetic nervous system; hormones ANTECEDENT EPISODES OF HYPOGLYCEMIA occurring 24 h before exercise have been found to blunt autonomic counterregulatory responses to subsequent prolonged moderate-intensity exercise (90 min at 50% V O 2 max ) by ϳ50% in both nondiabetic (8) and type 1 diabetes mellitus (T1DM) (19) individuals. In fact, it seems that this relationship is reciprocal; that is, recent antecedent episodes of prolonged moderate-intensity exercise have also been found to blunt autonomic counterregulatory responses during subsequent hypoglycemia occurring 24 h later in healthy (17, 30) and T1DM subjects (33). However, clinically, exercise-induced hypoglycemia has been reported to occur within 2 h after exercise.Although acute exercise-induced hypoglycemia in T1DM may at least partially stem from iatrogenic causes (i.e., in balance of subcutaneous insulin and metabolic needs), we (13) have demonstrated that morning hypoglycemia could acutely reduce neuroendocrine and symptom responses to subsequent, same-day, afternoon hypoglycemia in nondiabetic individuals. Des...

Aging of rats results in slower activities of calcium transport by cardiac calcium adenosinetriphosphatase (ATPase) of the sarcoplasmic reticulum (SR) and mitochondrial cytochrome oxidase (COX). These enzyme activities are faster after exercise training of previously sedentary old rats. Our purpose was to determine whether the expression of the genes encoding SR calcium ATPase (SERCA2a) or COX is altered by exercise training. Old (24-mo-old) male Fischer 344 rats were assigned to SO (sedentary old) or EO (exercised old) groups and compared with younger (12-mo-old) sedentary rats (SM). EO rats were trained on a treadmill for 8-10 wk. SERCA2a and COX mRNAs were lower (P < 0.05) in SO compared with SM and EO, whereas glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and cardiac alpha-actin mRNAs were similar across groups. The immunoreactive protein contents of cardiac calcium ATPase, cytochrome c, sarcomeric actin, and GAPDH followed the changes, when observed, in mRNA contents. Thus pretranslational mechanisms may be modified in some genes during aging and exercise training of previously sedentary old rats.

OBJECTIVETo determine the pharmacokinetic and pharmacodynamic dose-response effects of insulin glargine administered subcutaneously in individuals with type 2 diabetes.RESEARCH DESIGN AND METHODSTwenty obese type 2 diabetic individuals (10 male and 10 female, aged 50 ± 3 years, with BMI 36 ± 2 kg/m2 and A1C 8.3 ± 0.6%) were studied in this single-center, placebo-controlled, randomized, double-blind study. Five subcutaneous doses of insulin glargine (0, 0.5, 1.0, 1.5, and 2.0 units/kg) were investigated on separate occasions using the 24-h euglycemic clamp technique.RESULTSGlargine duration of action to reduce glucose, nonessential fatty acid (NEFA), and β-hydroxybutyrate levels was close to or >24 h for all four doses. Increases in glucose flux revealed no discernible peak and were modest with maximal glucose infusion rates of 9.4, 6.6, 5.5, and 2.8 μmol/kg/min for the 2.0, 1.5, 1.0, and 0.5 units/kg doses, respectively. Glargine exhibited a relatively hepatospecific action with greater suppression (P < 0.05) of endogenous glucose production (EGP) compared with little or no increases in glucose disposal.CONCLUSIONA single subcutaneous injection of glargine at a dose of ≥0.5 units/kg can acutely reduce glucose, NEFA, and ketone body levels for 24 h in obese insulin-resistant type 2 diabetic individuals. Glargine lowers blood glucose by mainly inhibiting EGP with limited effects on stimulating glucose disposal. Large doses of glargine have minimal effects on glucose flux and retain a relatively hepatospecific action in type 2 diabetes.

Background: Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath's four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results: Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18-20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions: Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

Acute increases of the key counterregulatory hormone epinephrine can be modified by a number of physiological and pathological conditions in type 1 diabetic patients (T1DM). However, it is undecided whether the physiological effects of epinephrine are also reduced in T1DM. Therefore, the aim of this study was to determine whether target organ (liver, muscle, adipose tissue, pancreas, cardiovascular) responses to epinephrine differ between healthy subjects and T1DM patients. Thirty-four age- and weight-matched T1DM (n = 17) and healthy subjects (n = 17) underwent two randomized, single-blind, 2-h hyperinsulinemic euglycemic clamp studies with (Epi) and without epinephrine infusion. Muscle biopsy was performed at the end of each study. Epinephrine levels during Epi were similar in all groups (4,039 +/- 384 pmol/l). Glucose (5.3 +/- 0.06 mmol/l) and insulin levels (462 +/- 18 pmol/l) were also similar in all groups during the glucose clamps. Glucagon responses to Epi were absent in T1DM and significantly reduced compared with healthy subjects. Endogenous glucose production during the final 30 min was significantly greater during Epi in healthy subjects compared with T1DM (8.4 +/- 1.3 vs. 4.4 +/- 0.6 micromol.kg(-1).min(-1), P = 0.041). Glucose uptake showed almost a twofold greater decrease with Epi in healthy subjects vs. T1DM (Delta31 +/- 2 vs. Delta17 +/- 2 nmol.kg(-1).min(-1), respectively, P = 0.026). Glycerol, beta-hydroxybutyrate, and nonesterified fatty acid (NEFA) all increased significantly more in T1DM compared with healthy subjects. Increases in systolic blood pressure were greater in healthy subjects, but reductions of diastolic blood pressure were greater in T1DM patients with Epi. Reduction of glycogen synthase was significantly greater during epinephrine infusion in T1DM vs. healthy subjects. In summary, despite equivalent epinephrine, insulin, and glucose levels, changes in glucose flux, glucagon, and cardiovascular responses were greater in healthy subjects compared with T1DM. However, T1DM patients had greater lipolytic responses (glycerol and NEFA) during Epi. Thus we conclude that there is a spectrum of significant in vivo physiological differences of epinephrine action at the liver, muscle, adipose tissue, pancreas, and cardiovascular system between T1DM and healthy subjects.