Muscle Glycogen Synthesis and Disposition of Infused Glucose in Humans With Reduced Rates of Insulin-Mediated Carbohydrate Storage

Young, Andrew; Bogardus, Clifton; Wolfe-Lopez, Deborah; Mott, David M.

doi:10.2337/diab.37.3.303

Cited by 58 publications

(8 citation statements)

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“…The reason for the association between elevated basal plasma lactate concentrations and insulin resistance, apparent in humans (45) as well as rats, is unclear, but the inability of muscle to store transported glucose as glycogen, a major determinant of insulin resistance (46)(47)(48), may be contributory, since transported glucose that is not stored and passes through the glycolytic pathway emerges as lactate if it cannot be oxidized. Consistent with this idea are studies in LA/N corpulent versus lean rats using the lactate clamp (49,50) in which an approximately fourfold higher lactate release, rather than reduced lactate clearance, explained the hyperlactemia in the insulin-resistant animals.…”

Section: Discussionmentioning

confidence: 97%

Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta).

Young¹,

Gedulin²,

Bhavsar³

et al. 1999

Diabetes

417

283

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Exendin-4 is a 39 amino acid peptide isolated from the salivary secretions of the Gila monster (Heloderma suspectum). It shows 53% sequence similarity to glucagon-like peptide (GLP)-1. Unlike GLP-1, exendin-4 has a prolonged glucose-lowering action in vivo. We compared the potency and duration of glucose-lowering effects of exendin-4 and GLP-1 in hyperglycemic db/db and ob/ob mice. Whereas reductions in plasma glucose of up to 35% vanished within 1 h with most doses of GLP-1, the same doses of exendin-4 resulted in a similar glucose-lowering effect that persisted for >4 h. Exendin-4 was 5,530-fold more potent than GLP-1 in db/db mice (effective doses, 50% [ED50s] of 0.059 microg/kg +/-0.15 log and 329 microg/kg+/-0.22 log, respectively) and was 5,480-fold more potent in ob/ob mice (ED50s of 0.136 microg/kg+/-0.10 log and 744 microg/kg+/-0.21 log, respectively) when the percentage fall in plasma glucose at 1 h was used as the indicator response. Exendin-4 dose-dependently accelerated glucose lowering in diabetic rhesus monkeys by up to 37% with an ED50 of 0.25 microg/kg +/-0.09 log. In two experiments in which diabetic fatty Zucker rats were injected subcutaneously twice daily for 5-6 weeks with doses of exendin-4 up to 100 microg x rat(-1) x day(-1) (approximately 250 microg/kg), HbA1c was reduced relative to saline-injected control rats. Exendin-4 treatment was also associated in each of these experiments with weight loss and improved insulin sensitivity, as demonstrated by increases of up to 32 and 49%, respectively, in the glucose infusion rate (GIR) in the hyperinsulinemic euglycemic clamp. ED50s for weight loss and the increase in clamp GIR were 1.0 microg/kg+/-0.15 log and 2.4 microg/kg+/-0.41 log, respectively. In conclusion, acute and chronic administration of exendin-4 has demonstrated an antidiabetic effect in several animal models of type 2 diabetes.

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Section: Discussionmentioning

confidence: 97%

Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta).

Young¹,

Gedulin²,

Bhavsar³

et al. 1999

Diabetes

417

283

View full text Add to dashboard Cite

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“…Specific activity of plasma tritiated water was determined by liquid scintillation counting of the protein-free supernatant (Somogyi filtrate) before and after evaporation to dryness. Because tritium on the C-3 position of glucose is lost to water during glycolysis, it can be assumed that plasma tritium is present in either tritiated water or 3-[ 3 H]glucose (11,13). Although tritium may also be released during fructose 6-phosphate cycling and/or pentose phosphate cycling, these pathways account for only a small percentage of glucose turnover (14).…”

Section: Methodsmentioning

confidence: 99%

Counterregulation of Hypoglycemia: Skeletal Muscle Glycogen Metabolism During Three Hours of Physiological Hyperinsulinemia in Humans

et al. 1995

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We examined the role of skeletal muscle in counterregulation of hypoglycemia (3.4 +/- 0.1 mmol/l) in 12 nondiabetic individuals (age 26 +/- 1 years, body mass index 24.2 +/- 0.7 kg/m2) during physiological hyperinsulinemia (280 +/- 25 pmol/l) compared with euglycemia (4.8 +/- 0.1 mmol/l). During hypoglycemia, hepatic glucose output (3-[3H]-glucose) was greater (7.72 +/- 2.72 mumol.kg-1.min-1, P < 0.01), glucose uptake was approximately 49% lower (21.20 +/- 3.55 mumol.kg-1.min-1, P < 0.005), and glucose clearance was reduced (P < 0.002) compared with euglycemia. Rates of flux of plasma-derived glucosyl units through glycolysis were similar in the two experiments, while glycogen synthetic rates were significantly reduced during hypoglycemia (P < 0.01) and accounted entirely for the reduction in glucose disposal. The insulin-induced activation of skeletal muscle glycogen synthase (reflected by Km decline by approximately 50% from 0.408 +/- 0.056 mmol/l and fractional velocity increase by approximately twofold from 21.8 +/- 2.7%) was completely abolished in hypoglycemia. In concert, glycogen phosphorylase activity increased during hypoglycemia by approximately 40% (P = 0.0001). Hypoglycemia resulted in seven- to eightfold increments in plasma epinephrine (P < 0.0001) and growth hormone (P < 0.001) and 40-60% increments in plasma glucagon (P < 0.005) and cortisol (P < 0.05). We conclude that, in this model of mild hypoglycemia of moderate duration, the majority of the glucose made available during the counterregulatory process (approximately 60-70%) is due to the limitation of glucose disposal, mostly via decreased glycogen synthetic activity in skeletal muscle.

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“…The nonoxidative pathway results in conversion of G6P to glycogen, where it resides as a storage form for recall later. A defect in glycogen synthesis has been identified as an early problem in NIDDM (36,37) and will be discussed later. A defect in glucose oxidation is also evident in diabetic patients with overt fasting hyperglycemia, but this appears to be a late development in the progression of NIDDM (38)(39)(40).…”

Section: Peripheral Glucose Utilization (Pgu)mentioning

confidence: 98%

Molecular Physiology and Genetics of NIDDM: Importance of Metabolic Staging

Granner

O’Brien²

1992

Diabetes Care

126

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Insulin resistance and beta-cell failure account for the complex clinical presentation of non-insulin-dependent diabetes mellitus (NIDDM). Insulin resistance primarily involves defective regulation of hepatic glucose production and the peripheral utilization of glucose. Considerable progress has been made in understanding the basic molecular biology, biochemistry, and physiology of these processes. Similarly, the mechanisms involved in insulin synthesis, processing, storage, and secretion are being elucidated. The relative contributions of insulin resistance and beta-cell failure are difficult to evaluate when the disease is fully established and clinically apparent but may be more obvious early, i.e., in people with impaired glucose tolerance or individuals at risk for developing the disease. The latter can be identified because there is a strong genetic determinant for NIDDM; the offspring of two diabetic parents have a markedly increased incidence of the disease. In addition to genetic factors, environmental components contribute to the multifactorial etiology of NIDDM. Efforts to establish the importance of these different factors will be assisted if a metabolic staging of NIDDM can be agreed on. This staging, which should correlate the pathophysiological events responsible for the transition from normal glucose tolerance to frank NIDDM with clinical status, would be based on what is known about insulin resistance and beta-cell function. Staging will also provide for a classification of the number of causes that lead to NIDDM, if indeed, there is more than one cause of the general phenotype. Strategies for defining the gene or genes responsible for NIDDM can be subsequently devised based on the temporal sequence of appearance of pathophysiological defects and what is known about the molecular biology of insulin action. Understanding the defective metabolic code that results in NIDDM will require the concerted efforts of investigators from various disciplines. This is used throughout the text to avoid confusion with those people who have impaired glucose tolerance but not NIDDM.

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Muscle Glycogen Synthesis and Disposition of Infused Glucose in Humans With Reduced Rates of Insulin-Mediated Carbohydrate Storage

Cited by 58 publications

References 0 publications

Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta).

Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta).

Counterregulation of Hypoglycemia: Skeletal Muscle Glycogen Metabolism During Three Hours of Physiological Hyperinsulinemia in Humans

Molecular Physiology and Genetics of NIDDM: Importance of Metabolic Staging

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