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Pathogenesis of fasting and postprandial hyperglycemia in type 2 diabetes: implications for therapy.

Rizza RA - Diabetes (2010)

Bottom Line: Delayed insulin secretion results in higher peak glucose concentrations particularly when suppression of glucagon is impaired, whereas insulin resistance prolongs the duration of hyperglycemia, which can be marked when both hepatic and extra-hepatic insulin resistance are present.I, as well as many other investigators, believe that such therapies are likely to be more effective and to have a lower risk than would occur if everyone were treated the same regardless of the underlying cause of their hyperglycemia.While we do not yet have sufficient knowledge to truly individualize therapy, in my opinion this approach will be the norm in the not too distant future.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. rizza.robert@mayo.edu

ABSTRACT
The objective of this research is to gain a greater understanding of the cause of fasting and postprandial hyperglycemia in people with type 2 diabetes. Endogenous glucose production is excessive before eating and fails to appropriately suppress after eating in people with type 2 diabetes. This is due in part to impaired insulin-induced suppression of endogenous glucose production, which is observed early in the evolution of type 2 diabetes. Increased rates of gluconeogenesis and perhaps glycogenolysis contribute to hepatic insulin resistance. Insulin-induced stimulation of hepatic glucose uptake and hepatic glycogen synthesis are reduced in people with type 2 diabetes primarily due to decreased uptake of extracellular glucose presumably because of inadequate activation of hepatic glucokinase. Delayed insulin secretion results in higher peak glucose concentrations particularly when suppression of glucagon is impaired, whereas insulin resistance prolongs the duration of hyperglycemia, which can be marked when both hepatic and extra-hepatic insulin resistance are present. The premise of these studies, as well as those performed by many other investigators, is that an understanding of the pathogenesis of type 2 diabetes will enable the development of targeted therapies that are directed toward correcting specific metabolic defects in a given individual. I, as well as many other investigators, believe that such therapies are likely to be more effective and to have a lower risk than would occur if everyone were treated the same regardless of the underlying cause of their hyperglycemia. While we do not yet have sufficient knowledge to truly individualize therapy, in my opinion this approach will be the norm in the not too distant future.

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Schematic portrayal of glucose metabolism in the blood, liver, and urine when labeled glucose and galactose are infused intravenously and acetaminophen is given by mouth in order to sample UDP-glucuronide in the urine (16). * and ** represent respectively labeled glucose and galactose.
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Figure 10: Schematic portrayal of glucose metabolism in the blood, liver, and urine when labeled glucose and galactose are infused intravenously and acetaminophen is given by mouth in order to sample UDP-glucuronide in the urine (16). * and ** represent respectively labeled glucose and galactose.

Mentions: Why is SGU decreased in people with type 2 diabetes? To gain insight into this question, Dr. Andy Basu used a method pioneered by the late Dr. Bernie Landau and colleagues (17) where acetaminophen is used to sample the hepatic uridine-5-diphosphate (UDP)-glucose pool during the infusion of labeled galactose. A schematic of this method is shown in Fig. 10. When infused in trace amounts, galactose is converted to UDP-galactose within hepatocyte, which in turn equilibrates with the UDP-glucose pool. Enrichment of UDP-glucose can be determined by giving acetaminophen and measuring the enrichment of UDP-glucuronide in the urine. Since UDP-glucose is the obligate precursor of glycogen, flux through the UDP-glucose pool into glycogen can be calculated. The enrichment of the intravenously infused glucose tracer also can be measured in the same manner allowing estimation of the proportion of the hepatic UDP-glucose pool that is derived from the uptake of extracellular glucose.


Pathogenesis of fasting and postprandial hyperglycemia in type 2 diabetes: implications for therapy.

Rizza RA - Diabetes (2010)

Schematic portrayal of glucose metabolism in the blood, liver, and urine when labeled glucose and galactose are infused intravenously and acetaminophen is given by mouth in order to sample UDP-glucuronide in the urine (16). * and ** represent respectively labeled glucose and galactose.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2963523&req=5

Figure 10: Schematic portrayal of glucose metabolism in the blood, liver, and urine when labeled glucose and galactose are infused intravenously and acetaminophen is given by mouth in order to sample UDP-glucuronide in the urine (16). * and ** represent respectively labeled glucose and galactose.
Mentions: Why is SGU decreased in people with type 2 diabetes? To gain insight into this question, Dr. Andy Basu used a method pioneered by the late Dr. Bernie Landau and colleagues (17) where acetaminophen is used to sample the hepatic uridine-5-diphosphate (UDP)-glucose pool during the infusion of labeled galactose. A schematic of this method is shown in Fig. 10. When infused in trace amounts, galactose is converted to UDP-galactose within hepatocyte, which in turn equilibrates with the UDP-glucose pool. Enrichment of UDP-glucose can be determined by giving acetaminophen and measuring the enrichment of UDP-glucuronide in the urine. Since UDP-glucose is the obligate precursor of glycogen, flux through the UDP-glucose pool into glycogen can be calculated. The enrichment of the intravenously infused glucose tracer also can be measured in the same manner allowing estimation of the proportion of the hepatic UDP-glucose pool that is derived from the uptake of extracellular glucose.

Bottom Line: Delayed insulin secretion results in higher peak glucose concentrations particularly when suppression of glucagon is impaired, whereas insulin resistance prolongs the duration of hyperglycemia, which can be marked when both hepatic and extra-hepatic insulin resistance are present.I, as well as many other investigators, believe that such therapies are likely to be more effective and to have a lower risk than would occur if everyone were treated the same regardless of the underlying cause of their hyperglycemia.While we do not yet have sufficient knowledge to truly individualize therapy, in my opinion this approach will be the norm in the not too distant future.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. rizza.robert@mayo.edu

ABSTRACT
The objective of this research is to gain a greater understanding of the cause of fasting and postprandial hyperglycemia in people with type 2 diabetes. Endogenous glucose production is excessive before eating and fails to appropriately suppress after eating in people with type 2 diabetes. This is due in part to impaired insulin-induced suppression of endogenous glucose production, which is observed early in the evolution of type 2 diabetes. Increased rates of gluconeogenesis and perhaps glycogenolysis contribute to hepatic insulin resistance. Insulin-induced stimulation of hepatic glucose uptake and hepatic glycogen synthesis are reduced in people with type 2 diabetes primarily due to decreased uptake of extracellular glucose presumably because of inadequate activation of hepatic glucokinase. Delayed insulin secretion results in higher peak glucose concentrations particularly when suppression of glucagon is impaired, whereas insulin resistance prolongs the duration of hyperglycemia, which can be marked when both hepatic and extra-hepatic insulin resistance are present. The premise of these studies, as well as those performed by many other investigators, is that an understanding of the pathogenesis of type 2 diabetes will enable the development of targeted therapies that are directed toward correcting specific metabolic defects in a given individual. I, as well as many other investigators, believe that such therapies are likely to be more effective and to have a lower risk than would occur if everyone were treated the same regardless of the underlying cause of their hyperglycemia. While we do not yet have sufficient knowledge to truly individualize therapy, in my opinion this approach will be the norm in the not too distant future.

Show MeSH
Related in: MedlinePlus