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Chapter 47: Diabetes Mellitus

As a hypothetical approach to treating the hyperglycemia associated with Type 2 diabetes, a drug firm proposes to develop an inhibitor of liver glycogen phosphorylase. What is the biochemical rationale for this approach to inducing hypoglycemia?

A. hepatic fatty acid oxidation will decrease leading to reduced energy production needed for gluconeogenesis

B. hepatocytes will have a reduced capacity to store glucose following meals

C. liver glucose output will be reduced early during fasting

D. the resultant increase in glycogen storage will inhibit glucose uptake by the liver leading to increased utilization in skeletal muscle

E. there will be an increase in hepatic gluconeogenesis

Answer C: During early fasting, as the level of glucose in the blood falls, the pancreas releases glucagon into the circulation to counter this drop. The major site of glucagon action is the liver. There it induces the activity of the glycogen phosphorylase leading to an increase in glucose release from glycogen stores. Thus, an inhibition of glycogen phsphorylase would limit the ability of the liver to provide glucose to the blood. Negatively affecting the activity of glycogen phosphorylase would not significantly affect the rate of hepatic fatty acid oxidation, skeletal muscle glucose usage, nor hepatic gluconeogenesis.

In Type 1 diabetes there is an associated hyperlipidemia. The best explanation for this is that the level of an enzyme important for fat homeostasis is reduced. Which of the following is this enzyme?

A. acyl-CoA dehydrogenase (eg, MCAD)

B. carnitine palmitoyltransferase I

C. glucose 6-phosphatase

D. hepatic lipase

E. lipoprotein lipase

Answer E: One of the effects of insulin is to increase the level of lipoprotein lipase (LPL) expression in endothelial cells. The lack of normal levels of circulating insulin in Type 1 diabetics results in impaired regulation of LPL levels. Reduced LPL contributes to the hyperlipidemia associated with T1D.

Obesity, genetic profile, and aging all contribute to the development of Type 2 diabetes. Of the following, which is the most important additive factor for these 3 conditions in the development of Type 2 diabetes?

A. elevated hepatic ketogenesis

B. elevated pancreatic glucagon secretion

C. impaired renal clearance of glucose

D. increased adipose tissue activity leading to hyperlipidemia

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