Effect of pancreatic transplantation on counterregulatory hormonal responses to hypoglycaemia.
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Animals↗
Biomedical subjects
R S Sherwin
Publications and source records attributed to R S Sherwin.
Insulin-like growth factor I stimulates cardiac myosin heavy chain and actin synthesis in the awake rat.
To determine the effect of insulin-like growth factor I (IGF-I) on cardiac contractile protein synthesis in vivo, we measured L-[ring-2, 6-3H]phenylalanine incorporation into myosin heavy chain and actin during intravenous infusions (4 h) of either saline or IGF-I (1 microgram. kg-1. min-1) in awake rats. After an overnight fast, IGF-I increased myosin synthesis by 29% compared with saline (11.5 +/- 0.8 vs. 8.9 +/- 0.6%/day, P < 0.01) and actin synthesis by 26% (7.2 +/- 0.3 vs. 5.7 +/- 0.3%/day, P < 0.01), with similar effects in left and right ventricles and a comparable effect on mixed cardiac protein. When amino acids were infused with IGF-I, a further increase in myosin synthesis was observed (P < 0.01). In fed rats, despite higher baseline synthesis rates than in fasted rats (P < 0. 01), IGF-I also increased the synthesis of myosin (12.3 +/- 0.5 vs. 9.9 +/- 0.5%/day, P < 0.01) and actin (8.8 +/- 0.3 vs. 7.5 +/- 0. 2%/day, P < 0.01) compared with saline. IGF-I infusion had no hypoglycemic effect and did not change heart rate or blood pressure. Thus relatively low-dose IGF-I has a direct action in vivo to acutely increase heart contractile protein synthesis in both fasted and fed awake rats.
Actins↗
Changes in free insulin-like growth factor-1 and leptin concentrations during acute metabolic decompensation in insulin withdrawn patients with type 1 diabetes.
UNLABELLED: To determine the effect of acute insulin withdrawal and its subsequent replacement on components of the insulin-like growth factor (IGF)-1 binding protein system and on circulating leptin levels in patients with type 1 diabetes. Seventeen patients (age 31 yr +/-10) with type 1 diabetes treated with continuous subcutaneous insulin infusion (HbA1c 7.6% +/-1.0) were studied. The protocol consisted of two phases: acute insulin withdrawal of up to 8 h followed by a further 2-h period of insulin replacement. For the first phase the basal insulin infusion was stopped (at 0300 h), and for the second a single dose of either regular human or insulin lispro was given subcutaneously (0.2 U/kg). Plasma insulin, glucose, growth hormone, glucagon, IGF-1, free IGF-1, IGFBP-1, -2, -3 and leptin were measured. RESULTS: After interruption of the basal insulin infusion, plasma free insulin levels fell from 60+/-12.0 pmol/L to 10.8+/-4.2 pmol/L, and plasma glucose rose from 5.6+/-0.4 mmol/L to 14.8+/-1.2 mmol/L (P< 0.01). During insulin withdrawal, IGFBP-1 increased by more than 6-fold (from 32+/-8 to 205+/-17 ng/mL, P<0.001), IGFBP-3 increased significantly (from 2631+/-118 to 3053+/-101 ng/mL, P<0.001), and total IGF-1 levels declined modestly (from 226+/-33 to 182+/-26 ng/mL, P<0.001). In contrast, free IGF-1 concentrations (0.72+/-0.22 ng/mL at baseline) were markedly suppressed during insulin withdrawal to values below the detection limit of the assay (0.08 ng/mL) in 15 of the 17 patients (P<0.001). Circulating plasma leptin declined markedly in females from 20+/-3 ng/mL to 11+/-2 ng/mL (P<0.0001) and in males from 10+/-2 ng/mL to 7+/-2 ng/mL (P<0.02). Within 2 h of insulin replacement, the changes in circulating concentrations of IGFBP-1 and IGFBP-3 were partially reversed, and free IGF-1 levels rebounded to 0.54+/-0.22 ng/mL (P<0.1 vs. insulin withdrawal). Growth hormone, glucagon, and IGFBP-2 levels did not change significantly throughout the study. Despite the rapid restoration of plasma insulin and substrate levels, circulating leptin levels continued to fall in the 2-h period after insulin replacement in both females and males. The marked reduction in circulating free IGF-1 after insulin withdrawal and its increase after insulin administration suggest that acute changes in IGFBP concentrations induced by insulin are important regulators of IGF-1 bioavailability in patients with type 1 diabetes. In both males and females, the rapid induction of severe insulin deficiency is associated with a consistent fall in plasma leptin levels.
Adolescent↗
Effects of recurrent hypoglycemia on brainstem function in diabetic BB rats: protective adaptation during acute hypoglycemia.
To determine whether antecedent recurrent hypoglycemia protects the brain from the adverse effects of a standardized hypoglycemic stimulus, we implanted electrodes in the inferior colliculi of diabetic rats to directly record inferior colliculi auditory-evoked potentials (ICEPs). Awake, chronically catheterized BB rats were studied after 2 weeks of insulin therapy designed to produce either chronic hyperglycemia (hyper-DM, glycated hemoglobin 7.6 +/- 0.4%) or recurrent hypoglycemia (hypo-DM, glycated hemoglobin 6.2 +/- 0.7%), and the results were compared with those observed in nondiabetic rats. When plasma glucose was lowered to and clamped at 2.8 mmol/l, the release of catecholamines was suppressed in the hypo-DM rats (epinephrine: 2.5 +/- 0.4 nmol/l) as compared with hyper-DM and the nondiabetic rats (9.3 +/- 2.3 and 32.7 +/- 6.1 nmol/l, respectively). ICEP latency was significantly delayed in hyper-DM and nondiabetic rats (P < 0.001), but it was unchanged in hypo-DM rats. A more pronounced reduction in plasma glucose (2.0 mmol/l), however, provoked a greater adrenergic response than that seen at 2.8 mmol/l and delayed ICEP latency by 23% in a separate group of hypo-DM animals. These data demonstrate that antecedent recurrent hypoglycemia attenuates the brainstem dysfunction associated with mild to moderate, but not severe, hypoglycemia in diabetic rats. This phenomenon may contribute to the alterations in hypoglycemia counterregulation seen in diabetic patients during intensive insulin therapy.
Acute Disease↗
Chronic hypoglycemia and diabetes impair counterregulation induced by localized 2-deoxy-glucose perfusion of the ventromedial hypothalamus in rats.
Previous studies have demonstrated that the ventromedial hypothalamus (VMH) plays a critical role in sensing and responding to systemic hypoglycemia. To evaluate the mechanisms of defective counterregulation caused by iatrogenic hypoglycemia and diabetes per se, we delivered 2-deoxy-glucose (2-DG) via microdialysis into the VMH to produce localized cellular glucopenia in the absence of systemic hypoglycemia. Three groups of awake chronically catheterized rats were studied: 1) nondiabetic (with a mean daily glucose [MDG] of 6.9 mmol/l) BB control rats (n = 5); 2) chronically hypoglycemic nondiabetic (3-4 weeks, with an MDG of 2.7 mmol/l) BB rats (n = 5); and 3) moderately hyperglycemic insulin-treated diabetic (with an MDG of 12.4 mmol/l) BB rats (n = 8). In hypoglycemic rats, both glucagon and catecholamine responses to VMH glucopenia were markedly (77-93%) suppressed. In diabetic rats, VMH 2-DG perfusion was totally ineffective in stimulating glucagon release. The epinephrine response, but not the norepinephrine response, was also diminished by 38% in the diabetic group. We conclude that impaired counterregulation after chronic hypoglycemia may result from alterations of the VMH or its efferent pathways. In diabetes, the capacity of VMH glucopenia to activate the sympathoadrenal system is only modestly diminished; however, the communication between the VMH and the alpha-cell is totally interrupted.
Animals↗
Induction of insulitis by glutamic acid decarboxylase peptide-specific and HLA-DQ8-restricted CD4(+) T cells from human DQ transgenic mice.
Insulin-dependent diabetes mellitus in humans is linked with specific HLA class II genes, e.g., HLA-DQA1*0301/ DQB1*0302 (DQ8). To investigate the roles of HLA-DQ8 molecules and glutamic acid decarboxylase (GAD) in disease development, we generated DQ8(+)/I-Abo transgenic mice expressing functional HLA-DQ8 molecules and devoid of endogenous mouse class II. DQ8(+)/I-Abo mice produced antigen-specific antibodies and formed germinal centers after immunization with GAD65 peptides. Two GAD peptide-specific (247-266 and 509-528), DQ8 restricted Th1 CD4(+) T cell lines, were generated from immunized DQ8(+)/I-Abo mice. They induced severe insulitis after adoptive transfer into transgene positive (but not negative) mice who were treated with a very low dose of streptozotocin that alone caused no apparent islet pathology. In addition to CD4, islet mRNA from these mice also showed expression of CD8, IFNgamma, TNFalpha, Fas, and Fas ligand. Our data suggest that a mild islet insult in the presence of HLA-DQ8 bearing antigen-presenting cells promotes infiltration of GAD peptide reactive T cells into the islet.
Animals↗
Widespread expression of an autoantigen-GAD65 transgene does not tolerize non-obese diabetic mice and can exacerbate disease.
Glutamic acid decarboxylase (GAD)65 is a pancreatic beta cell autoantigen implicated as a target of T cells that initiate and sustain insulin-dependent diabetes mellitus (IDDM) in humans and in non-obese diabetic (NOD) mice. In an attempt to establish immunological tolerance toward GAD65 in NOD mice, and thereby to test the importance of GAD in IDDM, we generated three lines transgenic for murine GAD65 driven by a major histocompatibility complex class I promoter. However, despite widespread transgene expression in both newborn and adult mice, T cell tolerance was not induced. Mononuclear cell infiltration of the islets (insulitis) and diabetes were at least as bad in transgenic mice as in nontransgenic NOD mice, and in mice with the highest level of GAD65 expression, disease was exacerbated. In contrast, the same transgene introduced into mouse strain, FvB, induced neither insulitis nor diabetes, and T cells were tolerant to GAD. Thus, the failure of NOD mice to develop tolerance toward GAD65 reflects at minimum a basic defect in central tolerance, not seen in animals not predisposed to IDDM. Hence, it may not be possible experimentally to induce full tolerance toward GAD65 in prediabetic individuals. Additionally, the fact that autoimmune infiltration in GAD65 transgenic NOD mice remained largely restricted to the pancreas, indicates that the organ-specificity of autoimmune disease is dictated by tissue-specific factors in addition to those directing autoantigen expression.
Animals↗
Decreased epinephrine responses to hypoglycemia during sleep.
BACKGROUND: In patients with type I diabetes mellitus, hypoglycemia occurs commonly during sleep and is frequently asymptomatic. This raises the question of whether sleep is associated with reduced counterregulatory-hormone responses to hypoglycemia. METHODS: We studied the counterregulatory-hormone responses to insulin-induced hypoglycemia in eight adolescent patients with type I diabetes and six age-matched normal subjects when they were awake during the day, asleep at night, and awake at night. In each study, the plasma glucose concentration was stabilized for 60 minutes at approximately 100 mg per deciliter (5.6 mmol per liter) and then reduced to 50 mg per deciliter (2.8 mmol per liter) and maintained at that concentration for 40 minutes. Plasma free insulin, epinephrine, norepinephrine, cortisol, and growth hormone were measured frequently during each study. Sleep was monitored by polysomnography. RESULTS: The plasma glucose and free insulin concentrations were similar in both groups during all studies. During the studies when the subjects were asleep, no one was awakened during the hypoglycemic phase, but during the final 30 minutes of the studies when the subjects were awake both the patients with diabetes and the normal subjects had symptoms of hypoglycemia. In the patients with diabetes, plasma epinephrine responses to hypoglycemia were blunted when they were asleep (mean [+/-SE] peak plasma epinephrine concentration, 70+/-14 pg per milliliter [382+/-76 pmol per liter]; P=0.3 for the comparison with base line), as compared with when they were awake during the day or night (238+/-39 pg per milliliter [1299+/-213 pmol per liter] P=0.004 for the comparison with base line, and 296+/-60 pg per milliliter [1616+/-327 pmol per liter], P=0.004, respectively). The patients' plasma norepinephrine responses were also reduced during sleep, whereas their plasma cortisol concentrations did not increase and their plasma growth hormone concentrations increased slightly. The patterns of counterregulatory-hormone responses in the normal subjects were similar. CONCLUSIONS: Sleep impairs counterregulatory-hormone responses to hypoglycemia in patients with diabetes and normal subjects.
Adolescent↗
GAD-reactive CD4+ Th1 cells induce diabetes in NOD/SCID mice.
Although glutamic acid decarboxylase (GAD) has been implicated in IDDM, there is no direct evidence showing GAD-reactive T cells are diabetogenic in vivo. To address this issue, 3-wk-old NOD mice received two injections of purified rat brain GAD; one mouse rapidly developed diabetes 3 wk later. Splenocytes from this mouse showed a proliferative response to purified GAD, and were used to generate a CD4+ T cell line, designated 5A, that expresses TCRs encoding Vbeta2 and Vbeta12. 5A T cells exhibit a MHC restricted proliferative response to purified GAD, as well as GAD65 peptide 524-543. After antigen-specific stimulation, 5A T cells secrete IFNgamma and TNFalpha/beta, but not IL-4. They are also cytotoxic against NOD-derived hybridoma cells (expressing I-Ag7) that were transfected with rat GAD65, but not nontransfected hybridoma cells. Adoptive transfer of 5A cells into NOD/SCID mice produced insulitis in all mice. Diabetes occurred in 83% of the mice. We conclude that GAD injection in young NOD mice may, in some cases, provoke diabetes due to the activation of diabetogenic T cells reactive to GAD65 peptides. Our data provide direct evidence that GAD65 autoimmunity may be a critical event in the pathogenesis of IDDM.
Adoptive Transfer↗
Mechanisms of the sympathoadrenal response to hypoglycemia.
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Adipose Tissue↗
Peroral gene therapy of lactose intolerance using an adeno-associated virus vector.
Gene therapy is usually reserved for severe and medically refractory disorders because of the toxicity, potential long-term risks and invasiveness of most gene transfer protocols. Here we show that an orally administered adeno-associated viral vector leads to persistent expression of a beta-galactosidase transgene in both gut epithelial and lamina propria cells, and that this approach results in long-term phenotypic recovery in an animal model of lactose intolerance. A gene 'pill' associated with highly efficient and stable gene expression might be a practical and cost-effective strategy for even relatively mild disorders, such as lactase deficiency.
Administration, Oral↗
Effect of insulin on glycerol production in obese adolescents.
Impaired stimulation of glucose metabolism and reduced suppression of lipolytic activity have both been suggested as important defects related to the insulin resistance of adolescent obesity. To further explore the relationship between these abnormalities, we studied seven obese [body mass index (BMI) 35 +/- 2 kg/m2] and seven lean (BMI 21 +/- 1 kg/m2) adolescents aged 13-15 yr and compared them with nine lean adults (aged 21-27 yr, BMI 23 +/- 1 kg/m2) during a two-step euglycemic-hyperinsulinemic clamp in combination with 1) a constant [2H5]glycerol (1.2 mg.m-2.min-1) infusion to quantify glycerol turnover and 2) indirect calorimetry to estimate glucose and net lipid oxidation rates. In absolute terms, basal glycerol turnover was increased and suppression by insulin was impaired in obese adolescents compared with both groups of lean subjects (P < 0.01). However, when the rates of glycerol turnover were adjusted for differences in body fat mass, the rates were similar in all three groups. Basal plasma free fatty acid (FFA) concentrations were significantly elevated, and the suppression by physiological increments in plasma insulin was impaired in obese adolescents compared with lean adults (P < 0.05). In parallel with the high circulating FFA levels, net lipid oxidation in the basal state and during the clamp was also elevated in the obese group compared with lean adults. Net lipid oxidation was inversely correlated with glucose oxidation (r = -0.50, P < 0.01). In conclusion, these data suggest that lipolysis is increased in obese adolescents (vs. lean adolescents and adults) as a consequence of an enlarged adipose mass rather than altered sensitivity of adipocytes to the suppressing action of insulin.
Adolescent↗
Effects of methyltestosterone on insulin secretion and sensitivity in women.
The frequent coexistence of hyperandrogenism and insulin resistance is well established; however, whether a cause and effect relationship exists remains to be established. In this study we tested the hypothesis that short-term androgen administered to women would induce insulin resistance. To test this hypothesis, regularly menstruating, nonobese women were studied before and during methyltestosterone administration (5 mg tid for 10-12 days) by the hyperglycemic (n=8) and euglycemic, hyperinsulinemic (n=7) clamp techniques. Short-term methyltestosterone administration had no significant effects on the fasting levels of glucose, insulin, c-peptide, glucagon, or glucose turnover. During the hyperglycemic clamp studies, the mean glucose level during the final hour was 203+/-2 and 201+/-1 mg/dL in the methyltestosterone and control studies, respectively. The insulin response to this hyperglycemic challenge was slightly but not significantly greater during methyltestosterone treatment (first phase 59+/-8 vs. 50+/-8 microU/mL in controls; second phase 74+/-9 vs. 67+/-9 microU/mL in controls; total insulin response 133+/-16 vs. 117+/-15 microU/mL in controls). In spite of this, glucose uptake was reduced from the control study value of 10.96+/-1.11 to 7.3+/-0.70 mg/kg/min by methyltestosterone (P < 0.05). The ratio of glucose uptake per unit of insulin was also significantly reduced from a control study value of 14.3+/-1.4 to 9.4+/-1.3 mg/kg/min per microU/mL x 100 during methyltestosterone administration. In the euglycemic hyperinsulinemic clamp studies, insulin was infused at rates of 0.25 and 1.0 mU/kg/min to achieve insulin levels of approximately 25 and 68 microU/mL, respectively. During low-dose insulin infusion, rates of endogenous hepatic glucose production were equivalently suppressed from basal values of 2.37+/-0.29 and 2.40+/-0.27 mg/kg/min to 0.88+/-0.25 and 0.77+/-0.26 mg/kg/min in the methyltestesterone and control studies respectively. Whole body glucose uptake during low-dose insulin infusion was minimally affected. During the high-dose insulin infusion, endogenous hepatic glucose production was nearly totally suppressed in both groups. However, whole body glucose uptake was reduced from the control value of 6.11+/-0.49 mg/kg/min to 4.93+/-0.44 mg/kg/min during methyltestosterone administration (P < 0.05). Our data demonstrate that androgen excess leads to the development of insulin resistance during both hyperglycemic and euglycemic hyperinsulinemia. These findings provide direct evidence for a relationship between hyperandrogenemia and insulin resistance, and its associated risk factors for cardiovascular disease.
Adult↗
The metabolic syndrome and insulin-like growth factor I regulation in adolescent obesity.
Although low GH levels are commonly seen in obese adults and children, the effects of obesity on the insulin-like growth factor (IGF)/IGF-binding protein (IGFBP) system have not been established. As GH and IGF-I normally increase during adolescence, we investigated the effects of obesity on circulating total and free IGF-I levels and IGFBP-1, -2, and -3 in 19 obese adolescents [14 +/- 1 yr old; body mass index (BMI), 34 +/- 3], 20 lean adolescents (14 +/- 1 yr old; BMI, 23 +/- 0.5), and 10 lean adults (22 +/- 0.7 yr; BMI, 22 +/- 0.7). Fasting plasma insulin levels were significantly greater in obese adolescents than in either lean group, whereas circulating IGFBP-1 levels were suppressed in an inverse relationship to basal insulin (r = -0.49; P < 0.01). Low IGFBP-1 levels were associated with normal to increased free IGF-I levels in obese adolescents, even though total IGF-I values were lower than those in lean adolescents. Basal GH and IGFBP-3 levels were also lower in obese vs. lean adolescents. Basal IGFBP-1 levels were markedly reduced in obese adolescents (14 +/- 3 ng/mL) vs. those in adolescents and adults. No further suppression of IGFBP-1 levels was observed in the obese group during a two-step 8 and 40 mU/m2 insulin clamp. In contrast, IGFBP-1 levels were promptly lowered in lean adults. Basal IGFBP-2 levels were significantly lower in both groups of adolescents vs. lean adults (P < 0.05), and IGFBP-2 levels did not change during euglycemic hyperinsulinemia. These data suggest that the compensatory hyperinsulinemia that characterizes adolescent obesity chronically suppresses levels of IGFBP-1, and low IGFBP-1 concentrations may serve to increase the bioavailability of free IGF-I, which may, in turn, contribute to lower circulating GH, total IGF-I, and IGFBP-3 concentrations.
Adolescent↗
Local ventromedial hypothalamus glucose perfusion blocks counterregulation during systemic hypoglycemia in awake rats.
The ventromedial hypothalamic nucleus (VMH) is necessary for the integrated hormonal response to hypoglycemia. To determine the role of the VMH as a glucose sensor, we performed experiments designed to specifically prevent glucopenia in the VMH, while producing hypoglycemia elsewhere. We used awake chronically catheterized rats, in which local VMH glucose perfusion (100 mM or 15 mM of D-glucose) was combined with a sequential euglycemic-hypoglycemic clamp. In two control groups the VMH was perfused either with (a) an iso-osmotic solution lacking glucose, or with (b) nonmetabolizable L-glucose (100 mM). During systemic hypoglycemia glucagon and catecholamine concentrations promptly increased in the control animals perfused with either 100 mM L-glucose or the iso-osmotic solution lacking glucose. In contrast, glucagon, epinephrine and norepinephrine release was inhibited in the animals in which the VMH was perfused with D-glucose; hormonal secretion was partially suppressed by the VMH perfusion with 15 mM D-glucose and suppressed by approximately 85% when the VMH was perfused with 100 mM D-glucose, as compared with the control groups. We conclude that the VMH must sense hypoglycemia for full activation of catecholamine and glucagon secretion and that it is a key glucose sensor for hypoglycemic counterregulation.
Animals↗
Microdialysis techniques in the study of brain and skeletal muscle.
Traditionally, plasma measurements have been used to monitor metabolic events and the actions of hormones that are actually taking place within tissue beds that are anatomically separated from the vascular compartment. It is generally assumed that the extracellular fluid (ECF) within metabolically active tissues is composed of substrates and hormones in concentrations that closely approximate those in plasma. Indeed, this view is implicit in non-steady-state tracer calculations. However, through the use of microdialysis techniques in the study of tissue metabolism this view is being challenged. Our data suggest that there may be substantial concentration gradients for a variety of fuels between plasma and ECF, i.e. fuels (e.g. glucose) removed from the circulation being lower and fuels (e.g. glycerol, lactate, some amino acids) produced by tissues being higher than plasma levels. In short, the metabolic milieu seen by individual tissues (and hormone receptors?) may, at least in some instances, be strikingly different from that in plasma, and as a result, plasma measurements by themselves may not appropriately define the contributions of specific tissues to metabolic events, and overlook the importance of metabolic processes which are largely restricted to individual tissue beds. Through the use of microdialysis as a means of directly sampling ECF from metabolically important body tissues and with the evolution of its use in animal and human research, this technique will continue to offer exciting new insights into tissue metabolism and to investigate fundamental issues that cannot be addressed by other methods.
Brain↗
Effects of insulin-like growth factor I on glucose metabolism in rats with liver cirrhosis.
To determine the effect of insulin-like growth factor I (IGF-I) on glucose metabolism in cirrhosis, a 2-h euglycemic clamp with IGF-I (0.65 nmol.kg-1.min-1) or insulin (12 pmol.kg-1.min-1) was performed in awake rats with carbon tetrachloride-induced liver cirrhosis. Rates of [3-3H]glucose-determined whole body glucose turnover were similar in the fasting state in cirrhotic and control rats (36.4 +/- 2.6 and 37.7 +/- 2.8 mumol.kg-1.min-1, respectively). In the control group, IGF-I and insulin had similar effects on turnover (81.6 +/- 27.0 and 76.1 +/- 9.9 mumol.kg-1.min-1), muscle glycogen synthesis (47.5 +/- 12.3 and 37.5 +/- 2.5 nmol.g muscle-1.min-1), and suppression of endogenous glucose production (EGP; -54 +/- 14 and -60 +/- 12%). Cirrhotic rats were markedly insulin resistant, reflected by a 43% reduction of turnover (43.8 +/- 9.4 mumol.g muscle-1.min-1; P = 0.03), a 73% reduction in muscle glycogen synthesis (10.2 +/- 3.4 nmol.g muscle-1.min-1; P < 0.0001), and a diminished suppression of EGP (-32 +/- 17% vs. control: -56 +/- 14%; P < 0.05). In contrast, during the IGF-I clamps, turnover increased threefold in the cirrhotic rats (P = 0.001), rates of muscle glycogen synthesis were 7.4 times higher than during the insulin stimulation (P < 0.0001), and EGP was suppressed by 80 +/- 12% (P < 0.05). In conclusion, insulin resistance in cirrhotic rats is mostly due to defects in insulin-stimulated muscle glycogen synthesis, and the ability of IGF-I to stimulate muscle glycogen synthesis as well as suppress EGP is maintained in cirrhotic rats. These findings suggest that alterations in both hepatic and peripheral glucose metabolism in patients with cirrhosis might be amenable to IGF-I therapy.
Animals↗
Acute incretin response to oral glucose is associated with stimulation of gastric inhibitory polypeptide, not glucagon-like peptide in young subjects.
Oral glucose induces a greater insulin response than i.v. glucose, a difference apparently due to the secretion of gut factors ("incretins"). Studies examining the mechanisms of this finding in human subjects are limited, however, because of differences in glucose profiles. To overcome this obstacle, we studied eight young nonobese subjects using the hyperglycemic clamp with and without superimposed ingestion of oral glucose. In both studies, glucose was acutely raised by 12.5 mg/dL above fasting values by the infusion of i.v. glucose and maintained at this level for 180 min. During the experimental study, but not the control, each subject ingested oral glucose (30 g) at 120 min, and the glucose infusion was adjusted to maintain the plasma glucose plateau. Plasma insulin responses were nearly identical during both studies until oral glucose was added. After oral glucose, both plasma insulin and C-peptide levels sharply increased by 45-55% above control values (p < 0.001), indicating a potentiation of insulin secretion rather than decreased hepatic extraction of insulin. Plasma gastric inhibitory polypeptide (GIP) levels increased significantly in response to oral glucose, whereas plasma levels of glucagon-like peptide-1 (7-37) were not affected. The time course of the rise in plasma GIP and insulin was nearly identical. We conclude that the GIP response to a modest oral glucose load may play an important physiologic role in glucose-stimulated insulin secretion in healthy young subjects.
Administration, Oral↗