Limits...
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.

Show MeSH

Related in: MedlinePlus

The contribution of extracellular and intracellular glucose to the hepatic UDP-glucose pool when glucose is clamped at ∼145 mg/dl and insulin at ∼300 pmol/l in people with or without type 2 diabetes (16). *P < 0.05 vs. no diabetes.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2963523&req=5

Figure 11: The contribution of extracellular and intracellular glucose to the hepatic UDP-glucose pool when glucose is clamped at ∼145 mg/dl and insulin at ∼300 pmol/l in people with or without type 2 diabetes (16). *P < 0.05 vs. no diabetes.

Mentions: As is evident in Fig. 11, UDP flux was lower in the people with diabetes implying decreased rates of hepatic glycogen synthesis. Of particular interest, the decrease in UDP glucose flux was entirely accounted for by a decrease in the rate of uptake of extracellular glucose with no difference in the proportion derived from intracellular sources. Since phosphorylation of glucose by glucokinase is the rate limiting step in the uptake of extracellular glucose by the liver (18,19), these data strongly suggest a defect in hepatic glucokinase activity. This conclusion is supported by studies that have shown decreased activity of this enzyme in people with type 2 diabetes (20) and by the observation that hepatic glucose uptake is reduced in people with genetic defects in glucokinase activation (21). Thus, people with type 2 diabetes have excessive rates of hepatic glucose release, impaired hepatic glucose uptake, decreased hepatic glycogen synthesis, and decreased uptake of extracellular glucose.


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

Rizza RA - Diabetes (2010)

The contribution of extracellular and intracellular glucose to the hepatic UDP-glucose pool when glucose is clamped at ∼145 mg/dl and insulin at ∼300 pmol/l in people with or without type 2 diabetes (16). *P < 0.05 vs. no diabetes.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 11: The contribution of extracellular and intracellular glucose to the hepatic UDP-glucose pool when glucose is clamped at ∼145 mg/dl and insulin at ∼300 pmol/l in people with or without type 2 diabetes (16). *P < 0.05 vs. no diabetes.
Mentions: As is evident in Fig. 11, UDP flux was lower in the people with diabetes implying decreased rates of hepatic glycogen synthesis. Of particular interest, the decrease in UDP glucose flux was entirely accounted for by a decrease in the rate of uptake of extracellular glucose with no difference in the proportion derived from intracellular sources. Since phosphorylation of glucose by glucokinase is the rate limiting step in the uptake of extracellular glucose by the liver (18,19), these data strongly suggest a defect in hepatic glucokinase activity. This conclusion is supported by studies that have shown decreased activity of this enzyme in people with type 2 diabetes (20) and by the observation that hepatic glucose uptake is reduced in people with genetic defects in glucokinase activation (21). Thus, people with type 2 diabetes have excessive rates of hepatic glucose release, impaired hepatic glucose uptake, decreased hepatic glycogen synthesis, and decreased 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