Fasting and postprandial liver glycogen content in patients with type 1 diabetes mellitus after successful pancreas–kidney transplantation with systemic venous insulin delivery

Stadler, Marietta; Krššák, Martin; Janković, Draženka; Göbl, Christian; Winhofer, Yvonne; Pacini, Giovanni; Bischof, Martin; Haidinger, Michael; Säemann, Marcus D.; Mühlbacher, Ferdinand; Korbonits, Márta; Baumgartner‐Parzer, Sabina; Luger, Anton; Prager, Rudolf; Anderwald, Christian; Krebs, Michael

doi:10.1111/cen.12146

Cited by 8 publications

(5 citation statements)

References 20 publications

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“…This process is crucial to blood glucose homeostasis because glycaemia is maintained by degradation of hepatic glycogen during a fasting state. As reported, even optimized systemic insulin substitution cannot resolve the defect in postprandial liver glycogen storage in type I diabetic patients 5. Here, we further investigated the hepatic glucose utilization induced by Pep‐PMS in diabetic rats, including hepatic glucose uptake and hepatic glycogen production.…”

Section: Resultsmentioning

confidence: 87%

“…Moreover, the synthesized hepatic glycogen is responsible for the maintenance of normoglycemia between meals. As reported, subcutaneous injection of insulin cannot resolve the defect in postprandial hepatic glycogen storage in type I diabetic patients 5. Oral delivery of exogenous insulin is preferred and promising because it can simulate the biodistribution of endogenous insulin, which satisfies the high portal‐to‐peripheral gradient.…”

Section: Introductionmentioning

confidence: 99%

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Liver‐Target and Glucose‐Responsive Polymersomes toward Mimicking Endogenous Insulin Secretion with Improved Hepatic Glucose Utilization

Wang

Fan

Yang

et al. 2020

Adv Funct Materials

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Oral insulin therapy that targets the liver and further mimics glucoseresponsive secretion holds promise for correcting defects in glucose metabolism caused by peripheral delivery. This work describes the construction of polymersomes (Pep-PMS), which are composed of glucose-responsive polymers decorated with peptides that readily bind to the ganglioside-monosialic acid (GM1) receptor in the intestinal epithelium. Pep-PMS are efficiently transported across the intestinal epithelium through GM1-mediated transcytosis, leading to their abundant accumulation in the liver. Moreover, Pep-PMS can efficiently encapsulate insulin in euglycemia and release them in hyperglycemia. Under hyperglycemic conditions, the Pep-PMS dissociate to release the encapsulated insulin in response to glucose oxidase (GOx)-induced H 2 O 2 . Surprisingly, the postprandial blood glucose levels of diabetic rats treated with Pep-PMS can be maintained even after being challenged by glucose administration. Hepatic glucose uptake and glycogen production are also elevated after treating diabetic rats with Pep-PMS, which is similar to glucose utilization in normal rats. Oral delivery systems that target the liver and serve as a reservoir for glucose-responsive insulin secretion may improve the therapeutic effect in people with diabetes.

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Section: Resultsmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Liver‐Target and Glucose‐Responsive Polymersomes toward Mimicking Endogenous Insulin Secretion with Improved Hepatic Glucose Utilization

Wang

Fan

Yang

et al. 2020

Adv Funct Materials

View full text Add to dashboard Cite

show abstract

“…G-6-Pas and FBP-1 are key enzymes responsible for gluconeogenesis, whereas hexokinase is responsible for glucose degradation [ 41 , 42 ]. Glycogen stores are significantly depleted in the muscles and livers of T1DM animals and humans due to a lack of insulin [ 43 , 44 , 45 , 46 ]. This was also documented in the livers of the diabetic rats in this study, which also showed lower stores of hepatic glycogen.…”

Section: Discussionmentioning

confidence: 99%

Phloretamide Prevent Hepatic and Pancreatic Damage in Diabetic Male Rats by Modulating Nrf2 and NF-κB

et al. 2023

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This study examined the effect of phloretamide, a metabolite of phloretin, on liver damage and steatosis in streptozotocin-induced diabetes mellitus (DM) in rats. Adult male rats were divided into two groups: control (nondiabetic) and STZ-treated rats, each of which was further treated orally with the vehicle phloretamide 100 mg or 200 mg. Treatments were conducted for 12 weeks. Phloretamide, at both doses, significantly attenuated STZ-mediated pancreatic β-cell damage, reduced fasting glucose, and stimulated fasting insulin levels in STZ-treated rats. It also increased the levels of hexokinase, which coincided with a significant reduction in glucose-6 phosphatase (G-6-Pase), and fructose-1,6-bisphosphatase 1 (PBP1) in the livers of these diabetic rats. Concomitantly, both doses of phloretamide reduced hepatic and serum levels of triglycerides (TGs) and cholesterol (CHOL), serum levels of low-density lipoprotein cholesterol (LDL-c), and hepatic ballooning. Furthermore, they reduced levels of lipid peroxidation, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), mRNA, and total and nuclear levels of NF-κB p65, but increased mRNA levels, total and nuclear levels of Nrf2, as well as levels of reduced glutathione (GSH), superoxide dismutase (SOD-1), catalase (CAT), and heme-oxygenase-1 (HO-1) in the livers of diabetic rats. All of these effects were dose-dependent. In conclusion, phloretamide is a novel drug that could ameliorate DM-associated hepatic steatosis via its powerful antioxidant and anti-inflammatory effects. Mechanisms of protection involve improving the β-cell structure and hepatic insulin action, suppressing hepatic NF-κB, and stimulating hepatic Nrf2.

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“…Those with insulindependent diabetes have been found in a number of investigations, although not all, to have lower postprandial levels of hepatic glycogen than normal control subjects (9,(39)(40)(41)(42). A difference in liver glycogen levels between subjects with diabetes without complications and individuals without diabetes is most evident after the third meal of the day (40,43), and this may explain why some studies quantifying only the postbreakfast glycogen levels may not observe a difference between subjects with diabetes compared with control subjects without diabetes. It is noteworthy that normal dogs with enhanced hepatic glycogen reserves (achieved via fructose administration during an AM period of hyperinsulinemia and hyperglycemia) exhibited a markedly improved counterregulatory response (enhanced glucagon and epinephrine secretion, coupled with a stimulation of net hepatic glucose release) during a PM period of hypoglycemia in comparison with animals under the same hypoglycemic conditions but in the absence of the AM fructose infusion (10).…”

Section: Discussionmentioning

confidence: 99%

Morning Hyperinsulinemia Primes the Liver for Glucose Uptake and Glycogen Storage Later in the Day

et al. 2018

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We observed that a 4-h morning (AM) duodenal infusion of glucose versus saline doubled hepatic glucose uptake (HGU) and storage during a hyperinsulinemic-hyperglycemic (HIHG) clamp that afternoon (PM). To separate the effects of AM hyperglycemia versus AM hyperinsulinemia on the PM response, we used hepatic balance and tracer ([3-H]glucose) techniques in conscious dogs. From 0 to 240 min, dogs underwent a euinsulinemic-hyperglycemic (GLC; = 7) or hyperinsulinemic-euglycemic (INS; = 8) clamp. Tracer equilibration and basal sampling occurred from 240 to 360 min, followed by an HIHG clamp (360-600 min; four times basal insulin, two times basal glycemia) with portal glucose infusion (4 mg ⋅ kg ⋅ min). In the HIHG clamp, HGU (5.8 ± 0.9 vs. 3.3 ± 0.3 mg ⋅ kg ⋅ min) and net glycogen storage (6.0 ± 0.8 vs. 2.9 ± 0.5 mg ⋅ kg ⋅ min) were approximately twofold greater in INS than in GLC. PM hepatic glycogen content (1.9 ± 0.2 vs. 1.3 ± 0.2 g/kg body weight) and glycogen synthase (GS) activity were also greater in INS versus GLC, whereas glycogen phosphorylase (GP) activity was reduced. Thus AM hyperinsulinemia, but not AM hyperglycemia, enhanced the HGU response to a PM HIHG clamp by augmenting GS and reducing GP activity. AM hyperinsulinemia can prime the liver to extract and store glucose more effectively during subsequent same-day meals, potentially providing a tool to improve glucose control.

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Fasting and postprandial liver glycogen content in patients with type 1 diabetes mellitus after successful pancreas–kidney transplantation with systemic venous insulin delivery

Abstract: In spite of normalized glycaemic control, postprandial liver glycogen content was reduced in T1DM-PKT with systemic venous drainage. Thus, not even optimized systemic insulin substitution is able to resolve the defect in postprandial liver glycogen storage seen in T1DM patients.

Cited by 8 publications

References 20 publications

Liver‐Target and Glucose‐Responsive Polymersomes toward Mimicking Endogenous Insulin Secretion with Improved Hepatic Glucose Utilization

Liver‐Target and Glucose‐Responsive Polymersomes toward Mimicking Endogenous Insulin Secretion with Improved Hepatic Glucose Utilization

Phloretamide Prevent Hepatic and Pancreatic Damage in Diabetic Male Rats by Modulating Nrf2 and NF-κB

Morning Hyperinsulinemia Primes the Liver for Glucose Uptake and Glycogen Storage Later in the Day

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