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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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Related in: MedlinePlus

Rates of endogenous glucose production (upper panel) and total body glucose disappearance (lower panel) observed during the final 30 min of a hyperinsulinemic clamp when glucose concentrations were clamped at ∼8 mmol/l in people with or without type 2 diabetes (15). *P < 0.05 vs. no diabetes.
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Figure 6: Rates of endogenous glucose production (upper panel) and total body glucose disappearance (lower panel) observed during the final 30 min of a hyperinsulinemic clamp when glucose concentrations were clamped at ∼8 mmol/l in people with or without type 2 diabetes (15). *P < 0.05 vs. no diabetes.

Mentions: Rates of endogenous glucose production present during the final 30 min of each insulin infusion are shown in the upper panel of Fig. 6. Endogenous glucose production was suppressed in the people who did not have diabetes when insulin was increased from 150 to 300 pmol with no further suppression being observed when insulin was subsequently increased to 600 pmol. In contrast, despite matched glucose and insulin concentrations, endogenous glucose production was higher in the diabetic subjects than in the nondiabetic subjects at insulin concentrations of 150 pmol/l indicating hepatic insulin resistance. Endogenous glucose production progressively decreased when insulin concentrations were increased to 300 and then to 600 pmol/l. Of note, while the rates of endogenous glucose production were slightly higher in the people with diabetes, the differences were no longer significant at insulin concentrations above 150 pmol/l. Thus, people with type 2 diabetes have hepatic insulin resistance. These data also explain why hepatic insulin resistance will be missed when insulin action only is assessed at high insulin concentrations. A different pattern is observed for glucose disappearance. As shown in the lower panel of Fig. 6, glucose disappearance progressively increased in both groups when insulin concentrations were increased from 150 to 300 to 600 pmol/l. However, glucose disappearance was lower in the people with diabetes at all three insulin concentrations.


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

Rizza RA - Diabetes (2010)

Rates of endogenous glucose production (upper panel) and total body glucose disappearance (lower panel) observed during the final 30 min of a hyperinsulinemic clamp when glucose concentrations were clamped at ∼8 mmol/l in people with or without type 2 diabetes (15). *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 6: Rates of endogenous glucose production (upper panel) and total body glucose disappearance (lower panel) observed during the final 30 min of a hyperinsulinemic clamp when glucose concentrations were clamped at ∼8 mmol/l in people with or without type 2 diabetes (15). *P < 0.05 vs. no diabetes.
Mentions: Rates of endogenous glucose production present during the final 30 min of each insulin infusion are shown in the upper panel of Fig. 6. Endogenous glucose production was suppressed in the people who did not have diabetes when insulin was increased from 150 to 300 pmol with no further suppression being observed when insulin was subsequently increased to 600 pmol. In contrast, despite matched glucose and insulin concentrations, endogenous glucose production was higher in the diabetic subjects than in the nondiabetic subjects at insulin concentrations of 150 pmol/l indicating hepatic insulin resistance. Endogenous glucose production progressively decreased when insulin concentrations were increased to 300 and then to 600 pmol/l. Of note, while the rates of endogenous glucose production were slightly higher in the people with diabetes, the differences were no longer significant at insulin concentrations above 150 pmol/l. Thus, people with type 2 diabetes have hepatic insulin resistance. These data also explain why hepatic insulin resistance will be missed when insulin action only is assessed at high insulin concentrations. A different pattern is observed for glucose disappearance. As shown in the lower panel of Fig. 6, glucose disappearance progressively increased in both groups when insulin concentrations were increased from 150 to 300 to 600 pmol/l. However, glucose disappearance was lower in the people with diabetes at all three insulin concentrations.

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