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Leptin therapy in insulin-deficient type I diabetesPortal Forum Anabolic diet carb load days Galerie my. Kniebeugen Ziel Gewicht kg: CF Mit Zitat antworten Re: Ist viel zu unterschiedlich wie der Einzelne darauf reagiert! Aber das ein ganzes Pint nicht unbedingt optimal ist, sollte sowieso klar sein, oder? Wieso haben schwarze immer so nen hammer rücken?
In nonobese diabetic mice with uncontrolled type 1 diabetes, leptin therapy alone or combined with low-dose insulin reverses the catabolic state through suppression of hyperglucagonemia. Additionally, it mimics the anabolic actions of insulin monotherapy and normalizes hemoglobin A1c with far less glucose variability. We show that leptin therapy, like insulin, normalizes the levels of a wide array of hepatic intermediary metabolites in multiple chemical classes, including acylcarnitines, organic acids tricarboxylic acid cycle intermediates , amino acids, and acyl CoAs.
In contrast to insulin monotherapy, however, leptin lowers both lipogenic and cholesterologenic transcription factors and enzymes and reduces plasma and tissue lipids. The results imply that leptin administration may have multiple short- and long-term advantages over insulin monotherapy for type 1 diabetes.
The discovery of insulin in 1 transformed type 1 diabetes mellitus T1DM from a uniformly fatal disease to a manageable disorder with a relatively normal but burdensome life for the patient. Despite the monumental dimensions of that achievement, it is now clear that, for several reasons, monotherapy with injected insulin cannot duplicate the metabolic homeostasis provided by endogenous insulin derived from pancreatic islets.
First, peripherally injected insulin cannot meet the high insulin requirements of its upstream targets, the alpha cells and hepatocytes, without exceeding the insulin requirements of its downstream targets, skeletal muscle and adipocytes.
Attempts to reconcile the inherent differences in insulin requirements of its target tissues may contribute to the glycemic lability that typifies the disease. Second, unopposed lipogenic action of insulin may also contribute to glycemic instability by intermittently promoting fatty acid FA -mediated insulin resistance 2 — 4 , which, in the long term, contributes to lipotoxic cardiomyopathy 5. Third, chronic hyperinsulinemia may enhance cholesterologenesis 6 and account for the high incidence of coronary artery disease in patients with T1DM 7 , 8.
Even when plasma lipid and lipoprotein levels are normal in patients with type 1 diabetes, the apoB-lipoproteins are cholesteryl ester-enriched and are potentially more atherogenic 9. In this report, we compare the therapeutic actions of insulin and leptin in a rodent model of T1DM, the nonobese diabetic NOD mouse.
We found that both hormones prevent ketoacidosis, cachexia, and death and that both restore hemoglobin A1c HbA1c to normal. In addition, they both reverse the catabolic state, which is reflected by normalization of a wide array of intermediary metabolites that accumulated in livers of mice with uncontrolled insulin deficiency.
However, the two hormones differ dramatically with respect to their effects on lipid metabolism: We find that recombinant leptin, either alone or combined with low-dose insulin therapy, provides equivalent or superior glycemic stability without the increase in body fat and up-regulation of cholesterologenic and lipogenic transcription factors and enzymes observed with insulin monotherapy.
These findings raise the possibility of a role for leptin supplementation in the treatment of human T1DM. They were compared with diabetic littermates treated with insulin by s. Untreated controls received PBS infusion by Alzet pump.
Like insulin treatment, leptin infusion lowered hemoglobin A1c to 3. The time required to restore normoglycemia with leptin therapy varied with the severity and duration of the disease, ranging from 1 day in the mice with the least severe diabetes to 7—9 days in mice with more severe diabetes of longer duration. Comparisons of various parameters in plasma of type 1 diabetic NOD mice. Mice were either untreated or treated with s.
A Plasma leptin levels. B Blood glucose levels. C Plasma FFA levels. The dotted lines mark the normal values. The leptin-treated mice lost 2. When pair-fed to the leptinized group, the PBS-treated mice lost 4. Insulin-treated mice gained 1. Body length in leptin-treated mice measured 8. These findings suggest that leptin-induced weight loss was at the expense of body fat rather than lean body mass.
Furthermore, with leptin, liver glycogen increased from 7. Indeed, the most striking differences between leptin and insulin therapies were in lipid metabolism. In addition to the lowering of FFA, other lipid abnormalities associated with insulin-treated T1DM were corrected by leptin therapy.
Liver TG averaged 6. TG concentrations in plasma and liver and expression levels of transcription factors and enzymes involved in lipogenesis and cholesterologenesis in livers of type 1 diabetic NOD mice treated either with s. A Plasma TG concentration. B Liver TG content. The broken horizontal lines indicate the relative expression level of the mRNA in nondiabetic control mice.
To determine the mechanism of the antilipogenic effect of leptin, we compared the expression of the lipogenic transcription factor, sterol regulatory element binding protein SREBP -1c, and several of its lipogenic target enzymes Fig.
Reduced insulin receptor substrate 2 IRS-2 mRNA is reportedly associated with insulin-stimulated lipogenesis and hepatic insulin resistance 11 ; indeed, it was almost twice as high in insulin-treated mice NS 12 Table 2.
There were two unexpected results. Second, CD36, the fatty acid transporter, was elevated in the PBS-treated group and lowered to near-normal values with insulin and leptin therapies Table 2. Coronary artery disease CAD , a common event in longstanding T1DM 8 , is generally attributed to the hyperglycemia of diabetes rather than to the hyperinsulinemia caused by its treatment.
Plasma glucagon levels and activation of its transcription factor, CREB, and a target enzyme in livers of type 1 diabetic NOD mice treated with s. D mRNA of phosphoenol pyruvate carboxykinase. We had previously shown that hepatic overproduction of glucose, ketones, and other catabolic manifestations of insulin deficiency cannot occur in the absence of hyperglucagonemia To determine if the antidiabetic effects of leptin might be mediated by glucagon suppression, which was suggested by Tuduri et al.
Thus, like insulin, leptin is a potent suppressor of glucagon. Glucagon suppression was associated with a reduction in phosphorylated cAMP response element binding protein CREB in the liver 18 , which was consistent with less glucagon action Fig. The mRNA of phosphoenol pyruvate carboxykinase, a prime gluconeogenic target of glucagon, was also reduced by leptin as well as insulin Fig.
P-STAT3, an indicator of direct leptin action, was increased in the livers of the leptin-treated but not insulin-treated mice, suggesting that leptin was acting directly on the liver Fig.
However, it is not clear how much of the hepatic action of leptin therapy is the result of glucagon suppression and how much is a direct insulin-like effect on the liver. Alloxanized wild-type controls became severely hyperglycemic, hyperketonemic, and cachectic unless treated with insulin. These findings indicate that the laboratory and clinical aberrations of severe insulin deficiency cannot occur in the absence of glucagon action. It further suggests that the leptin-mediated reversal of the insulin-deficiency phenotype in T1DM rodents could be caused by glucagon suppression alone.
Nevertheless, other actions of leptin in addition to glucagon suppression may well have contributed to the normalization of the metabolic state in the absence of insulin. To understand more completely the intracellular metabolic effects of leptin vs.
Remarkably, despite the enormous differences in lipid partitioning and metabolism described for the two hormone therapies, leptin and insulin were virtually identical in their abilities to reduce to normal the elevations of hepatic metabolite levels across all of the classes of analytes surveyed Fig. Taken together, our findings suggest that restoration to normal of intermediates of lipid metabolism was achieved by reactivation of lipogenesis in the case of insulin and by stimulation of lipid oxidation in the case of leptin.
Leptin also mimicked many other anticatabolic effects of insulin in the NOD mouse. A Acyl carnitines reflecting branch-chain amino acid metabolism and ketone production. B Long-chain acyl Co As and acyl carnitines Inset. C Branch-chain amino acids. Of metabolites measured, 67 were abnormal in untreated diabetes.
Of these, 55 were corrected or improved by both hormones. Three were corrected by leptin but not insulin. Three were corrected by insulin but not leptin. The remainder were not corrected. Although leptin monotherapy normalized the metabolic dysfunction in NOD mice with T1DM, a regimen without any insulin would not be approved for treatment in humans with this disease. We, therefore, compared the effects of insulin alone or supplemented with insulin at 0. With insulin monotherapy at the 0.
With the low 0. Liver TG content on this bihormonal regimen was 6. A Comparison of plasma glucose levels in type 1 diabetic NOD mice treated with twice daily injection of insulin alone at a total dose of 0. B Evidence that much lower doses of infused leptin without insulin are also effective in reducing the hyperglycemia of T1DM. Blood glucose levels of diabetic NOD mice treated for 20 days with leptin monotherapy by osmotic infusion pump are shown.
The human equivalent of doses of leptin employed in the foregoing rodent studies Fig. However, these high doses had been selected to simulate the adenovirally induced hyperleptinemia employed by Yu et al. To determine if lower leptin doses equivalent to those that could be practically employed in humans could also effectively reverse the metabolic abnormalities of insulin deficiency, we infused much lower doses through an infusion pump.
We found that after 1 week of priming doses of leptin ranging from 96 to 9. Monotherapy with insulin has transformed a previously fatal illness into a livable one, but injected hormone has not approached endogenous insulin in either the quality or quantity of life that it makes possible.
Quality of life is impaired by the frequent glucose monitoring and multiple insulin injections required to minimize the glycemic instability and its clinical consequences.
Peripherally injected insulin can meet all of these disparate needs only with insulin doses that far exceed the needs of peripheral sites, causing hypoglycemia. Another contributing factor to glycemic instability is lability of FFA levels A surge of FFA, released whenever insulin falls beneath the antilipolytic threshold, can flood the targets of insulin and make them resistant to its action 21 — 23 , thus promoting hyperglycemia. As for quantity of life, life expectancy with T1DM is reduced, not only by diabetes-specific microvascular diseases but also by macrovascular complications that are not specific to diabetes.
Of the latter, CAD and other atheromatous disorders have been linked to hyperinsulinemia, both endogenous and exogenous In addition, chronic hyperinsulinemia could contribute to lipotoxic complications present in the late stages of the diabetes. The ability of leptin to potentiate insulin in diabetes has been previously shown 25 , Recently, we reported that adenovirally induced hyperleptinemia could restore rodents with total insulin deficiency to good health Although this showed that there was an alternative to insulin in the treatment of insulin deficiency, it did not disclose the mechanism of the benefits or set the stage for translation to humans with T1DM, in whom adenoviral gene therapy is not an option.
This report indicates that injection of recombinant leptin can not only prevent the metabolic consequences of insulin deficiency like adenovirally induced hyperleptinemia but that it may eliminate certain underappreciated adverse consequences of insulin monotherapy.
Most strikingly, it shows in T1DM mice that leptin inhibits lipogenesis, increases FA oxidation, and thus, reduces tissue lipids while reducing factors involved in cholesterol biosynthesis. Furthermore, it suppresses hyperglucagonemia and mimics the anabolic effects of insulin on protein and carbohydrate metabolism, which restores a wide array of metabolic intermediates to normal in the liver.
Between 2 and 8 days of starting the infusion of recombinant leptin, the severe hyperglycemia and ketonuria are corrected, and the relentless catabolic course is reversed in every mouse that was treated Fig. Within 2 days, the markedly elevated FFA levels fall to one-half the levels of insulin-treated mice.
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