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Type I Diabetes Mellitus (Insulin‐Dependent Diabetes Mellitus)

Robert A. Rizza, Michael D. Jensen, K. Sreekumaran Nair

10.1002/cphy.cp070236

Source: Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism

Originally published: 2001

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Pathogenesis of Type I Diabetes
2 Effect of Type I Diabetes on Carbohydrate Metabolism
2.1 Insulin Secretion and Action
2.2 Postabsorptive and Postprandial Carbohydrate Metabolism
3 Effects of Type I Diabetes and Its Treatment on Fatty Acid Metabolism
3.1 Adipose Tissue
3.2 Postabsorptive FFA Metabolism
3.3 Postprandial FFA Availability
3.4 Effects of Exercise on Adipose Tissue Lipolysis
3.5 Regulation of Lipolysis During Hypoglycemia
4 Effects Of Type I Diabetes on Protein Metabolism
4.1 Regulation of Body Protein Mass, Amino Acid Levels and Nitrogen Balance
4.2 Effect of Insulin on Protein Balance and Interaction of Insulin with Other Hormones and Substrates
4.3 Effects of Insulin on Whole‐Body Protein Dynamics
4.4 Effect of Insulin on Amino Acid Transamination
4.5 Effect of Insulin on Regional Protein Dynamics
4.6 Effect of Insulin on the Synthesis Rates of Specific Proteins
4.7 Impact of Type I Diabetes on Protein Metabolism
Figure 1. Figure 1.

Stages in the development of diabetes mellitus. The stages of diabetes are listed from left to right and hypothetical beta‐cell mass is plotted against age.

[From Eisenbarth 71.]
Figure 2. Figure 2.

Isotopically determined glucose utilization rates during hy‐perinsulinemic euglycemic clamps as determined with [614C] glucose; [33H] glucose; and [23H] glucose. The utilization rates are plotted versus insulin concentrations observed in the diabetic (open circles) and non‐diabetic (solid circles) subjects.

[From Bell et al. 257.]
Figure 3. Figure 3.

Plasma insulin, glucose, and counterregulatory hormone concentrations in response to insulin‐induced hypoglycemia in diabetic patients (solid circles, solid lines) and nondiabetic subjects (open circles, dotted lines). Insulin was infused from 0 through 60 min (28 mU/m2). Diabetic patients were rendered euglycemic by overnight I.V. infusion of insulin, and the basal insulin infusion rate required to maintain euglycemia from ‐60 to 0 min was continued through 60 min (A): diabetic patients with diabetes duration of less than 1 mo; (B): diabetic patients with diabetes duration of 1–5 yrs; (C): 5 diabetic patients with diabetes duration of 14–31 yrs. *P<0.05, diabetics versus nondiabetics.

[From Bolli et al. 26.]
Figure 4. Figure 4.

Blood glucose, glucagon, and insulin levels during intermittent stimulation of glucagon produced by infusion of arginine in insulin‐dependent diabetic and nondiabetic subjects. Intermittent increase in glucagon causes only transient increase in glucose concentrations in nondiabetic individuals, whereas intermittent increase in glucagon causes a progressive rise in glucose concentration in the diabetic individuals.

[From Rizza et al. 207.]
Figure 5. Figure 5.

Effect of hourly pulses of growth hormone on plasma glucose concentration in individuals with type I diabetes mellitus. The amount of insulin given was kept constant throughout. Three individuals developed hypoglycemia following discontinuation of the growth hormone infusion. Their values (R) are shown separately.

[From Press et al. 196.]
Figure 6. Figure 6.

Glucose concentrations observed at end of 30 min insulin infusion in either nondiabetic (NL) or insulin‐dependent subjects versus the mean plasma epinephrine concentrations are plotted. In control studies, insulin secretion was permitted to vary, whereas in islet clamp studies insulin concentrations were matched by means of somatostatin and insulin infusions.

[From Berk et al. 18.]
Figure 7. Figure 7.

Glucose and insulin concentrations observed in type I diabetic subjects, when they were either insulin deficient (ID) or treated with appropriate amounts of insulin given as continuous subcutaneous insulin infusion (CSII), and healthy nondiabetic subjects. A mixed meal was ingested at time zero.

[From Pehling et al. 193.]
Figure 8. Figure 8.

Systemic appearance of ingested glucose (left) and rates of endogenous glucose production (right) were observed in type I diabetic subjects when they were either insulin deficient (ID) or when appropriate amounts of insulin were given as a continuous subcutaneous insulin infusion (CSII). Results observed in healthy nondiabetic subjects are shown for comparison. The meal was taken at 0 min.

[From Pehling et al. 193.]
Figure 9. Figure 9.

Simple model describing whole‐body protein dynamics in humans. In this model, proteins in different tissues of the body are assigned to one single compartment. Size of pool is determined by balance between protein synthesis and breakdown. Free amino acids in different body compartments (intracellular, interstitial‐extracellular, and plasma) are assigned to one pool. Amino acid pool is determined not only by balance of protein breakdown and synthesis, but also by protein ingestion during meals and amino acid catabolism. Certain (nonessential) amino acids also are synthesized in the body. Nitrogen excretion is a measure of irreversible loss of amino acids and is often used as an index of net protein loss in the body.
Figure 10. Figure 10.

Increase in urinary nitrogen excretion during the periods of insulin withdrawal demonstrated in two type I diabetic patients. Insulin replacement promptly reverses this increased nitrogen excretion.

[From Archley et al. (7).]
Figure 11. Figure 11.

Twenty‐six to thirty weeks of insulin treatment increased total‐body potassium (TBK) (a measure of body cell mass and total‐body nitrogen (TBN) in diabetic patients, indicating a net increase in body protein content 246.

[From Arner et al. 4.]
Figure 12. Figure 12.

Whole‐body leucine phenylalanine and tyrosine kinetics in type I diabetic patients. * Denotes significant (<0. 05) change. A: leucine ‐carbon flux representing protein breakdown. Leucine is an essential amino acid and 1‐carbon atom of leucine is labeled in these studies. The carboxyl (1‐carbon) moiety is not synthesized in the body and therefore the dilution of carboxyl label in the postabsorptive state occurs when unlabeled leucine appear from protein breakdown (leucine appearance). Similarly, phenylalanine and tyrosine flux values represent protein breakdown (both of these are essential amino acids). Insulin treatment decreased the appearance rates of leucine, phenylalanine, and tyrosine and, therefore, presumably, protein breakdown in these insulin‐deprived type I diabetic patients. B: leucine‐nitrogen flux (representing both protein breakdown and leucine transamination). C: Leucine transamination. Leucine → KIC → denotes deamination and KIC → leucine denotes ream‐ination. Leucine‐nitrogen flux, and leucine conversion to KIC and back to leucine are accelerated during insulin deprivation (P<0.01). Transamination process allows leucine to transfer nitrogen for synthesis of alanine and glutamine.

[From Nair et al. 173.]
Figure 13. Figure 13.

Whole body estimates of protein synthesis from nonoxidative leucine disposal and phenylalanine disappearance rate unaccounted for by phenylalaine conversion to tyrosine (Phe → Protein). In both cases there was higher protein synthesis, although the magnitude of increase was smaller than that of protein breakdown (in the same situations) during insulin deprivation.

[From Nair et al. 176.]
Figure 14. Figure 14.

Leucine oxidation and leucine oxidation values normalized for leucine flux and leucine transamination to KIC (KIC appearance rate) are given in the upper panel. Increased leucine oxidation occurs during insulin deprivation. When leucine oxidation was normalized for KIC (precursor of leucine oxidation) appearance rate from leucine, there was a lower leucine oxidation during insulin deprivation than during insulin treatment indicating that increased transamination of leucine to KIC that stimulated increased leucine oxidation.

[From Nair et al. 176.]
Figure 15. Figure 15.

Protein dynamics across splanchnic bed and leg based on phenylalanine‐tyrosine model. Protein breakdown (protein → phenylalanine) calculated in this model is based on dilution of L [ring‐2H5] phenylalanine across splanchnic bed (femoral artery vs. hepatic vein) and muscle bed (femoral artery vs. femoral vein). The portion of whole‐body protein breakdown not accounted for by splanchnic bed or muscle occurs in tissues other than splanchnic and muscle tissues. Higher protein breakdown occurred in all tissues during insulin deprivation than during insulin treatment. When percent increase in protein breakdown was estimated, skeletal muscle was largely responsible for the increase in whole‐body protein breakdown.

The lower panel gives protein synthesis (phenylalanine → protein) data. Protein synthesis in splanchnic bed is calculated based on the phenylalanine model from the difference of phenylalanine disposal and phenylalanine conversion rates. In this model, it is assumed that phenylalanine disappears from the compartment (splanchnic bed) either by its incorporation into protein or by its catabolic pathway via conversion to tyrosine. Since phenylalanine is not catabolized in skeletal muscle its only known fate is its incorporation into protein. So, protein synthesis (phenylalanine → proteins) in leg is phenylalanine disposal rate across leg.

Whole‐body protein synthesis was higher during insulin deprivation than during insulin treatment (P<0.01). All of the increase in whole‐body protein synthesis occurred in splanchnic bed. Insulin‐induced decline in whole‐body protein synthesis occurred entirely due to decline in splanchnic bed. Muscle protein synthesis did not change, but the relative contribution of muscle to whole body protein synthesis increased during insulin treatment.

[From Nair et al. 176.]
Figure 16. Figure 16.

Amino acid balances across leg and splanchnic bed. A negative balance of several amino acids and KIC across leg indicates net release of these amino acids from leg. Insulin significantly reduced this. A net uptake of amino acids occurred across splanchnic bed which was reduced by insulin treatment.

[From Nair et al. 176.]
Figure 17. Figure 17.

Synthesis rates of albumin and fibrinogen in type I diabetic patients during insulin deprivation (I‐) and during insulin treatment (I‐). During insulin deprivation albumin synthesis rate decreased, whereas fibrinogen synthesis rate increased.

[From De Feo et al. 53.]


Figure 1.

Stages in the development of diabetes mellitus. The stages of diabetes are listed from left to right and hypothetical beta‐cell mass is plotted against age.

[From Eisenbarth 71.]


Figure 2.

Isotopically determined glucose utilization rates during hy‐perinsulinemic euglycemic clamps as determined with [614C] glucose; [33H] glucose; and [23H] glucose. The utilization rates are plotted versus insulin concentrations observed in the diabetic (open circles) and non‐diabetic (solid circles) subjects.

[From Bell et al. 257.]


Figure 3.

Plasma insulin, glucose, and counterregulatory hormone concentrations in response to insulin‐induced hypoglycemia in diabetic patients (solid circles, solid lines) and nondiabetic subjects (open circles, dotted lines). Insulin was infused from 0 through 60 min (28 mU/m2). Diabetic patients were rendered euglycemic by overnight I.V. infusion of insulin, and the basal insulin infusion rate required to maintain euglycemia from ‐60 to 0 min was continued through 60 min (A): diabetic patients with diabetes duration of less than 1 mo; (B): diabetic patients with diabetes duration of 1–5 yrs; (C): 5 diabetic patients with diabetes duration of 14–31 yrs. *P<0.05, diabetics versus nondiabetics.

[From Bolli et al. 26.]


Figure 4.

Blood glucose, glucagon, and insulin levels during intermittent stimulation of glucagon produced by infusion of arginine in insulin‐dependent diabetic and nondiabetic subjects. Intermittent increase in glucagon causes only transient increase in glucose concentrations in nondiabetic individuals, whereas intermittent increase in glucagon causes a progressive rise in glucose concentration in the diabetic individuals.

[From Rizza et al. 207.]


Figure 5.

Effect of hourly pulses of growth hormone on plasma glucose concentration in individuals with type I diabetes mellitus. The amount of insulin given was kept constant throughout. Three individuals developed hypoglycemia following discontinuation of the growth hormone infusion. Their values (R) are shown separately.

[From Press et al. 196.]


Figure 6.

Glucose concentrations observed at end of 30 min insulin infusion in either nondiabetic (NL) or insulin‐dependent subjects versus the mean plasma epinephrine concentrations are plotted. In control studies, insulin secretion was permitted to vary, whereas in islet clamp studies insulin concentrations were matched by means of somatostatin and insulin infusions.

[From Berk et al. 18.]


Figure 7.

Glucose and insulin concentrations observed in type I diabetic subjects, when they were either insulin deficient (ID) or treated with appropriate amounts of insulin given as continuous subcutaneous insulin infusion (CSII), and healthy nondiabetic subjects. A mixed meal was ingested at time zero.

[From Pehling et al. 193.]


Figure 8.

Systemic appearance of ingested glucose (left) and rates of endogenous glucose production (right) were observed in type I diabetic subjects when they were either insulin deficient (ID) or when appropriate amounts of insulin were given as a continuous subcutaneous insulin infusion (CSII). Results observed in healthy nondiabetic subjects are shown for comparison. The meal was taken at 0 min.

[From Pehling et al. 193.]


Figure 9.

Simple model describing whole‐body protein dynamics in humans. In this model, proteins in different tissues of the body are assigned to one single compartment. Size of pool is determined by balance between protein synthesis and breakdown. Free amino acids in different body compartments (intracellular, interstitial‐extracellular, and plasma) are assigned to one pool. Amino acid pool is determined not only by balance of protein breakdown and synthesis, but also by protein ingestion during meals and amino acid catabolism. Certain (nonessential) amino acids also are synthesized in the body. Nitrogen excretion is a measure of irreversible loss of amino acids and is often used as an index of net protein loss in the body.



Figure 10.

Increase in urinary nitrogen excretion during the periods of insulin withdrawal demonstrated in two type I diabetic patients. Insulin replacement promptly reverses this increased nitrogen excretion.

[From Archley et al. (7).]


Figure 11.

Twenty‐six to thirty weeks of insulin treatment increased total‐body potassium (TBK) (a measure of body cell mass and total‐body nitrogen (TBN) in diabetic patients, indicating a net increase in body protein content 246.

[From Arner et al. 4.]


Figure 12.

Whole‐body leucine phenylalanine and tyrosine kinetics in type I diabetic patients. * Denotes significant (<0. 05) change. A: leucine ‐carbon flux representing protein breakdown. Leucine is an essential amino acid and 1‐carbon atom of leucine is labeled in these studies. The carboxyl (1‐carbon) moiety is not synthesized in the body and therefore the dilution of carboxyl label in the postabsorptive state occurs when unlabeled leucine appear from protein breakdown (leucine appearance). Similarly, phenylalanine and tyrosine flux values represent protein breakdown (both of these are essential amino acids). Insulin treatment decreased the appearance rates of leucine, phenylalanine, and tyrosine and, therefore, presumably, protein breakdown in these insulin‐deprived type I diabetic patients. B: leucine‐nitrogen flux (representing both protein breakdown and leucine transamination). C: Leucine transamination. Leucine → KIC → denotes deamination and KIC → leucine denotes ream‐ination. Leucine‐nitrogen flux, and leucine conversion to KIC and back to leucine are accelerated during insulin deprivation (P<0.01). Transamination process allows leucine to transfer nitrogen for synthesis of alanine and glutamine.

[From Nair et al. 173.]


Figure 13.

Whole body estimates of protein synthesis from nonoxidative leucine disposal and phenylalanine disappearance rate unaccounted for by phenylalaine conversion to tyrosine (Phe → Protein). In both cases there was higher protein synthesis, although the magnitude of increase was smaller than that of protein breakdown (in the same situations) during insulin deprivation.

[From Nair et al. 176.]


Figure 14.

Leucine oxidation and leucine oxidation values normalized for leucine flux and leucine transamination to KIC (KIC appearance rate) are given in the upper panel. Increased leucine oxidation occurs during insulin deprivation. When leucine oxidation was normalized for KIC (precursor of leucine oxidation) appearance rate from leucine, there was a lower leucine oxidation during insulin deprivation than during insulin treatment indicating that increased transamination of leucine to KIC that stimulated increased leucine oxidation.

[From Nair et al. 176.]


Figure 15.

Protein dynamics across splanchnic bed and leg based on phenylalanine‐tyrosine model. Protein breakdown (protein → phenylalanine) calculated in this model is based on dilution of L [ring‐2H5] phenylalanine across splanchnic bed (femoral artery vs. hepatic vein) and muscle bed (femoral artery vs. femoral vein). The portion of whole‐body protein breakdown not accounted for by splanchnic bed or muscle occurs in tissues other than splanchnic and muscle tissues. Higher protein breakdown occurred in all tissues during insulin deprivation than during insulin treatment. When percent increase in protein breakdown was estimated, skeletal muscle was largely responsible for the increase in whole‐body protein breakdown.

The lower panel gives protein synthesis (phenylalanine → protein) data. Protein synthesis in splanchnic bed is calculated based on the phenylalanine model from the difference of phenylalanine disposal and phenylalanine conversion rates. In this model, it is assumed that phenylalanine disappears from the compartment (splanchnic bed) either by its incorporation into protein or by its catabolic pathway via conversion to tyrosine. Since phenylalanine is not catabolized in skeletal muscle its only known fate is its incorporation into protein. So, protein synthesis (phenylalanine → proteins) in leg is phenylalanine disposal rate across leg.

Whole‐body protein synthesis was higher during insulin deprivation than during insulin treatment (P<0.01). All of the increase in whole‐body protein synthesis occurred in splanchnic bed. Insulin‐induced decline in whole‐body protein synthesis occurred entirely due to decline in splanchnic bed. Muscle protein synthesis did not change, but the relative contribution of muscle to whole body protein synthesis increased during insulin treatment.

[From Nair et al. 176.]


Figure 16.

Amino acid balances across leg and splanchnic bed. A negative balance of several amino acids and KIC across leg indicates net release of these amino acids from leg. Insulin significantly reduced this. A net uptake of amino acids occurred across splanchnic bed which was reduced by insulin treatment.

[From Nair et al. 176.]


Figure 17.

Synthesis rates of albumin and fibrinogen in type I diabetic patients during insulin deprivation (I‐) and during insulin treatment (I‐). During insulin deprivation albumin synthesis rate decreased, whereas fibrinogen synthesis rate increased.

[From De Feo et al. 53.]
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Article Title: Type I Diabetes Mellitus (Insulin‐Dependent Diabetes Mellitus)
 

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Robert A. Rizza, Michael D. Jensen, K. Sreekumaran Nair. Type I Diabetes Mellitus (Insulin‐Dependent Diabetes Mellitus). Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 1093-1114. First published in print 2001. doi: 10.1002/cphy.cp070236