Protein intake does not affect insulin sensitivity in normal weight cats (original) (raw)
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Diabetes, 2003
Liver IGF-1 deficient (LID) mice demonstrate a 75% reduction in circulating IGF-1 levels and a corresponding fourfold increase in growth hormone (GH) levels. At 16 weeks of age, LID mice demonstrate, using the hyperinsulinemic-euglycemic clamp, insulin insensitivity in muscle, liver, and fat tissues. In contrast, mice with a gene deletion of the acid-labile subunit (ALSKO) demonstrate a 65% reduction in circulating IGF-1 levels, with normal GH levels and no signs of insulin resistance. To further clarify the relative roles of increased GH and decreased IGF-1 levels in the development of insulin resistance, we crossed the two mouse lines and created a double knockout mouse (LID؉ ALSKO). LID؉ALSKO mice demonstrate a further reduction in circulating IGF-1 levels (85%) and a concomitant 10-fold increase in GH levels. Insulin tolerance tests showed an improvement in insulin responsiveness in the LID؉ALSKO mice compared with controls; LID mice were very insulin insensitive. Surprisingly, insulin sensitivity, while improved in white adipose tissue and in muscle, was unchanged in the liver. The lack of improvement in liver insulin sensitivity may reflect the absence of IGF-1 receptors or increased triglyceride levels in the liver. The present study suggests that whereas GH plays a major role in inducing insulin resistance, IGF-1 may have a direct modulatory role.
Journal of Endocrinology, 2001
At supraphysiological levels, IGF-I bypasses some forms of insulin resistance and has been proposed as a therapeutic agent in the treatment of diabetes. Unfortunately, side effects of high-dose IGF-I (100-250 µg/kg) have precluded its clinical use. Low-dose IGF-I (40-80 µg/kg), however, shows minimal side effects but has not been systematically evaluated. In our previous study under conditions of declining glucose, low-dose IGF-I infusion was more effective in stimulating glucose utilization, but less effective in suppressing glucose production and lipolysis than low-dose insulin. However, under conditions of hyperglycemia, we could not observe any differential effects between high-dose infusions of IGF-I and insulin. To determine whether the differential effects of IGF-I and insulin are dose-related or related to the prevailing glucose level, 3 h glucose clamps were performed in the same animal model as in the previous studies, i.e. the moderately hyperglycemic (175 mg/dl) insulin-infused depancreatized dog, with additional infusions of low-dose IGF-I (67·8 µg/kg, i.e. 29·1 µg/kg bolus plus 0·215 µg/kg per min infusion; n=5) or insulin 49·5 mU/kg (9 mU/kg bolus plus 0·45 mU/kg per min; n=7). As in the previous study under conditions of declining glucose, low-dose IGF-I had significant metabolic effects in vivo, in our model of complete absence of endogenous insulin secretion. Glucose production was similarly suppressed with both IGF-I and insulin, by 54 3 and 56 2% .. (P=NS) respectively. Glucose utilization was stimulated to the same extent (IGF-I 5·2 0·2, insulin 5·5 0·3 mg/kg per min, P=NS). Glucagon, free fatty acid, glycerol, alanine and betahydroxybutyrate, were suppressed, while lactate and pyruvate levels were raised, similarly with IGF-I and insulin. We conclude that: (i) differential effects of IGF-I and insulin may be masked under hyperglycemic conditions, independent of the hormone dose; (ii) low-dose IGF-I has no selective advantage over additional insulin in suppressing glucose production and lipolysis, nor in stimulating glucose utilization during hyperglycemia and subbasal insulin infusion when insulin secretion is absent, as in type 1 diabetes mellitus.
Metabolic Actions of IGF-I in Normal Physiology and Diabetes
Synopsis Insulin-like growth factor-I (IGF-I) is closely related to insulin but has distinct metabolic actions. IGF-I is an important stimulant of protein synthesis in muscle but it also stimulates free fatty acid utilization. Important indirect effects of IGF-I that influence metabolism include suppression of growth hormone secretion and at supraphysiologic concentrations suppression of insulin secretion. IGF-I actions are regulated by IGF binding proteins and in obesity and metabolic syndrome there is major dysregulation of IGF binding protein secretion resulting in alterations in the concentration of free IGF-I and IGF-I actions. In type 1 diabetes, IGF-I synthesis is markedly impaired and in type 2 diabetes multiple changes occur in IGF-I actions including sensitization to its mitogenic actions in some target tissues. Administration of IGF-I to patients with extreme insulin resistance results in improvement in glycemic control and IGF-I has been shown to be associated with lowering glucose and enhancing insulin sensitivity in both type 1 and type 2 diabetes. However diabetics are also quite sensitive to stimulation of side effects in response to IGF-I and this has greatly limited its usefulness as a hypoglycemic agent. IGF-I coordinately links growth hormone and insulin actions as well as having direct effects on intermediary metabolism.
2010
To determine the role of IGF-binding proteins in mediating the direct effects of recombinant human IGF-I on insulin requirements in type 1(insulin-dependent) diabetes mellitus, overnight changes in IGF-I, IGF-II, and IGF-binding protein-1, -2, and -3, collected under euglycemic conditions, were compared in nine subjects after double blind, randomized, sc administration of recombinant human IGF-I (40 g/kg) or placebo at 1800 h. On both nights a somatostatin analog infusion (300 ng/kg⅐h) suppressed endogenous GH production, and three timed discrete GH pulses (total, 0.029 IU/kg⅐night) ensured identical GH levels.
International Journal of Diabetes in Developing Countries, 2008
We studied the correlations between fasting and post-lunch serum IGF-I concentrations, and insulin resistance and insulin sensitivity in subjects with various degrees of glucose tolerance. MATERIALS AND METHODS: A total of 12 nondiabetic subjects, 09 subjects with impaired glucose tolerance (IGT) and 18 patients with newly diagnosed type-2 diabetes of either sex (mean age, 46 years) were recruited. None of the participants received any drug treatment at the commencement of the study. Fasting as well as post-lunch blood samples were collected from all the subjects and anthropometric and biochemical parameters were analyzed. RESULTS: Fasting serum IGF-I concentrations were negatively correlated with fasting serum glucose, insulin, C-peptide, triglycerides, total LDL and VLDL cholesterol, homeostatic model assessment of insulin resistance (HOMA-IR), and age. Fasting serum IGF-I concentrations were positively correlated with fasting blood HDL cholesterol and homeostatic model assessment of insulin sensitivity (HOMA-S) in only diabetic subjects. Post-lunch serum IGF-I concentrations were positively correlated with HDL and LDL cholesterol. Correlations with HOMA-S with these metabolic anthropometric variables were of similar magnitude and direction as that of IGF-I concentrations. IGF-I concentrations were signiÞ cantly lower in the subjects with World Health Organizationdefined metabolic syndrome compared with the subjects without metabolic syndrome (P < 0.0001). CONCLUSIONS: Our data indicate that IGF-I could be a useful marker in the insulin resistance syndrome. The post-lunch low-IGF-I levels help in better identiÞ cation of subjects at risk for type-2 diabetes mellitus and cardiovascular disease.
Liver-Specific igf-1 Gene Deletion Leads to Muscle Insulin Insensitivity
Diabetes, 2001
To study the metabolic consequences of IGF-I deficiency, we used the liver IGF-I-deficient (LID) mouse model. The LID mice show a marked reduction (ϳ75%) in circulating IGF-I and elevated growth hormone (GH) levels. Interestingly, LID mice show a fourfold increase in serum insulin levels (2.2 vs. 0.6 ng/ml in control mice) and abnormal glucose clearance after insulin injection. Fasting blood glucose levels and those after a glucose tolerance test were similar between the LID mice and their control littermates. Thus, the high levels of circulating insulin enable the LID mice to maintain normoglycemia in the presence of apparent insulin insensitivity. Insulin-induced autophosphorylation of the insulin receptor and tyrosine phosphorylation of insulin receptor substrate (IRS)-1 were absent in muscle, but were normal in liver and white adipose tissue of the LID mice. In contrast, IGF-I-induced autophosphorylation of its cognate receptor and phosphorylation of IRS-1 were normal in muscle of LID mice. Thus, the insulin insensitivity seen in the LID mice is muscle specific. Recombinant human IGF-I treatment of the LID mice caused a reduction in insulin levels and an increase in insulin sensitivity. Treatment of the LID mice with GH-releasing hormone antagonist, which reduces GH levels, also increased insulin sensitivity. These data provide evidence of the role of circulating IGF-I as an important component of overall insulin action in peripheral tissues.
Journal of Clinical Investigation, 1989
To elucidate the acute metabolic actions of insulin-like growth factor I (IGF-I), we administered a primed (250 ,ug/kg), continuous (5 gg/kg. min) infusion of human recombinant (Thr 59) IGF-I or saline to awake, chronically catheterized 24-h fasted rats for 90 min. IGF-I was also infused while maintaining euglycemia (glucose clamp technique) and its effects were compared to those of insulin. IGF-I infusion caused a twofold rise in IGF-I levels and a 75-85% decrease in plasma insulin. When IGF-I alone was given, plasma glucose fell by 30-40 mg/dl (P < 0.005) due to a transient twofold increase (P < 0.05) in glucose uptake; hepatic glucose production and plasma FFA levels remained unchanged. IGF-I infusion with maintenance of euglycemia produced a sustained rise in glucose uptake and a marked stimulation of 13-3Hjglucose incorporation into tissue glycogen, but still failed to suppress glucose production and FFA levels. IGF-I also produced a generalized 30-40% reduction in plasma amino acids, regardless of whether or not hypoglycemia was prevented. This was associated with a decrease in leucine flux and a decline in the incorporation of i1-'4Clleucine into muscle and liver protein (P < 0.05). When insulin was infused in a dosage that mimicked the rise in glucose uptake seen with IGF-I, nearly identical changes in amino acid metabolism occurred. However, insulin suppressed glucose production by 65% and FFA levels by 40% (P < 0.001). Furthermore, insulin was less effective than IGF-I in promoting glycogen synthesis. We conclude that (a) IGF-I produces hypoglycemia by selectively enhancing glucose uptake; (b) IGF-I is relatively ineffective in suppressing hepatic glucose production or FFA levels; and (c) IGF-I, like insulin, lowers circulating amino acids by reducing protein breakdown rather than by stimulating protein synthesis. Thus, IGF-I's metabolic actions in fasted rats are readily distinguished from insulin.
Diabetes, 2000
Type 1 diabetes is associated with abnormalities of the growth hormone (GH)-IGF-I axis. Such abnormalities include decreased circulating levels of IGF-I. We studied the effects of IGF-I therapy (40 µg · kg -1 · day -1 ) on protein and glucose metabolism in adults with type 1 diabetes in a randomized placebo-controlled trial. A total of 12 subjects participated, and each subject was studied at baseline and after 7 days of treatment, both in the fasting state and during a hyperinsulinemiceuglycemic amino acid clamp. Protein and glucose metabolism were assessed using infusions of [1-13 C]leucine and [6-6-2 H 2 ]glucose. IGF-I administration resulted in a 51% rise in circulating IGF-I levels (P < 0.005) and a 56% decrease in the mean overnight GH concentration (P < 0.05). After IGF-I treatment, a decrease in the overnight insulin requirement (0.26 ± 0.07 vs. 0.17 ± 0.06 U/kg, P < 0.05) and an increase in the glucose infusion requirement were observed during the hyperinsulinemic clamp (~67%, P < 0.05). Basal glucose kinetics were unchanged, but an increase in insulin-stimulated peripheral glucose disposal was observed after IGF-I therapy (37 ± 6 vs. 52 ± 10 µmol · kg -1 · min -1 , P < 0.05). IGF-I administration increased the basal metabolic clearance rate for leucine (~28%, P < 0.05) and resulted in a net increase in leucine balance, both in the basal state and during the hyperinsulinemic amino acid clamp (-0.17 ± 0.03 vs. -0.10 ± 0.02, P < 0.01, and 0.25 ± 0.08 vs. 0.40 ± 0.06, P < 0.05, respectively). No changes in these variables were recorded in the subjects after administration of placebo. These findings demonstrated that IGF-I replacement resulted in significant alterations in glucose and protein metabolism in the basal and insulinstimulated states. These effects were associated with increased insulin sensitivity, and they underline the major role of IGF-I in protein and glucose metabolism in type 1 diabetes. -J. have received research funding and honoraria for speaking engagements from Pharmacia and Upjohn.
Effects of insulin-like growth factor-I on glucose tolerance, insulin levels, and insulin secretion
Journal of Clinical Investigation, 1992
Insulin-like growth factor-I (IGF-I)1 and insulin interact with related receptors to lower plasma glucose and to exert mitogenic effects. Recombinant human IGF-I (rhIGF-I) was recently shown to decrease serum levels of insulin and C-peptide in fasted normal subjects without affecting plasma glucose levels. In this study we have investigated in six healthy volunteers the responses of glucose, insulin, and C-peptide levels to intravenous rhIGF-I infusions (7 and 14 gg/kgh) during standard oral glucose tolerance tests (oGTT) and meal tolerance tests (MITT), respectively. Glucose tolerance remained unchanged during the rhIGF-I infusions in the face of lowered insulin and C-peptide levels. The decreased insulin/glucose-ratio presumably is caused by an enhanced tissue sensitivity to insulin. The lowered area under the insulin curve during oGTT and MITT as a result ofthe administration of rhIGF-I were related to the fasting insulin levels during saline infusion (oGTF: r = 0.825, P < 0.05; MITT: r = 0.895, P < 0.02). RhIGF-I, however, did not alter the ratio between C-peptide and insulin, suggesting that the metabolic clearance of endogenous insulin remained unchanged. In conclusion, rhIGF-I increased glucose disposal and directly suppressed insulin secretion. RhIGF-I probably increased insulin sensitivity as a result of decreased insulin levels and suppressed growth hormone secretion. RhIGF-I, therefore, may be therapeutically useful in insulin resistance of type 2 diabetes, obesity, and hyperlipidemia.