Type II Diabetes Case File

Type II Diabetes Case File

Eugene C.Toy, MD, William E. Seifert, Jr., PHD, Henry W. Strobel, PHD, Konrad P. Harms, MD

❖ CASE 22

A 50-year-old Hispanic female presents to your clinic with complaints of excessive thirst, fluid intake, and urination. She denies any urinary tract infection symptoms. She reports no medical problems, but has not seen a doctor in many years. On examination she is an obese female in no acute distress. Her physical exam is otherwise normal. The urinalysis revealed large glucose, and a serum random blood sugar level was 320 mg/dL.

◆ What is the most likely diagnosis?

◆ What other organ systems can be involved with the disease?

◆ What is the biochemical basis of this disease?

ANSWERS TO CASE 22: TYPE II DIABETES

Summary: 50-year-old obese Hispanic female presents with polydipsia, polyphagia, and urinary frequency and elevated random blood sugar of 320 mg/dL.

◆ Diagnosis: Type II diabetes.

◆ Other organ systems involved: Cardiovascular, eye, peripheral nerves, gastrointestinal, kidney.

◆ Biochemical basis: Insulin resistance as a result of a postinsulin receptor defect. The insulin levels are normal or increased as compared with normal individuals; however, the insulin is not “recognized,” and thus the glucose levels remain elevated.

CLINICAL CORRELATION

Diabetes mellitus is characterized by elevated blood glucose levels. It is composed of two types depending on the pathogenesis. Type I diabetes is characterized by insulin deficiency and usually has its onset during childhood or teenage years. This is also called ketosis-prone diabetes. Type II diabetes is caused by insulin resistance and usually has elevated insulin levels, and it is diagnosed in the adult years. Type II diabetes is far more common than type I diabetes. Risk factors include obesity, family history, sedentary life style, and, in women, hyperandrogenic states or anovulation.

Diabetes mellitus is now recognized as one of the most common and significant diseases facing Americans. It is estimated that 1 of 4 children born today will become diabetic in their lifetime because of obesity and inactivity. Also, it has been noted that diabetes has a severe effect on blood vessels, particularly in the pathogenesis of atherosclerosis (blockage of arteries by lipids and plaque), which can lead to myocardial infarction or stroke. Diabetes mellitus is treated as equivalent to a prior cardiovascular event in its risk for future atherosclerotic disease. Diabetes is also associated with immunosuppression, renal insufficiency, blindness, neuropathy, and other metabolic disorders.

APPROACH TO INSULIN AND GLUCOSE

Objectives

1. Understand the role of insulin on carbohydrate metabolism.

2. Be aware of the role of glucagon on carbohydrate metabolism.

3. Know about the processes of gluconeogenesis and glycogenolysis.

Definitions

Diabetes mellitus: An endocrine disease characterized by an elevated blood glucose concentration. There are two major forms of diabetes mellitus: type I, or insulin-dependent, and type II, or non insulin-dependent. Type I is caused by a severe lack or complete absence of insulin. Type II is caused by resistance to insulin, that is, an inability to respond to physiologic concentrations of insulin.

Fructose 2,6-bisphosphate: A metabolite of fructose 6-phosphate produced by the bifunctional enzyme 6-phosphofructokinase-2/fructose bisphosphatase-2 (PFK-2/FBPase-2). It serves as an allosteric effector

that activates 6-phosphofructokinase-1 and inhibits fructose bisphosphatase- 1, thus stimulating the movement of glucose through the glycolytic pathway and inhibiting gluconeogenesis.

Glucagon: A polypeptide hormone synthesized and secreted by the α-cells of the islets of Langerhans in the pancreas. Glucagon is released in response to low blood glucose levels and stimulates glycogenolysis and gluconeogenesis in the liver.

Insulin: A polypeptide hormone synthesized and secreted by the β-cells of the islets of Langerhans in the pancreas. Insulin is released in response to elevations in blood glucose and promotes the uptake of glucose into cells by increasing the number of GLUT 4 glucose transporters on cell surfaces.

Protein kinase A: An enzyme that will phosphorylate target proteins. It is activated by increased cAMP concentration in the cell that is a response to the activation of adenylate cyclase by binding of certain hormones on cell surfaces.

DISCUSSION

Every cell in the human body uses glucose as an energy source. Indeed, certain cells have an obligate requirement for glucose to meet their energetic demands (e.g., erythrocytes). Neurons, although can use alternative fuel sources under extreme conditions (e.g., ketone bodies during prolonged starvation), have a strong preference toward glucose utilization. Circulating levels of glucose must therefore be maintained sufficiently high to meet the energy demands of the body. Chronic elevations in blood glucose levels are also detrimental, being associated with oxidative stress and glycation of cellular proteins. It has been suggested that the latter mediate many of the complications associated with chronic hyperglycemia, such as diabetic microvascular disease and retinopathy.

Despite diurnal variations in meal times, blood glucose levels are normally maintained within a narrow range. This is made possible in large part by the counter regulatory actions of the peptide hormones insulin and glucagon. Insulin, secreted by the β-cells of pancreatic islets when blood glucose levels increase, promotes glucose utilization and represses endogenous glucose production (Figure 22-1a). In contrast, glucagon, secreted by the α-cells of pancreatic islets when blood glucose levels are low, represses glucose utilization and promotes endogenous glucose production (Figure 22-1b). A careful balance between the actions of insulin and glucagon therefore help maintain blood glucose levels within a normal range.

Insulin receptors are essentially expressed ubiquitously, in large part as a result of the mitogenic actions of this peptide hormone. In terms of glucose metabolism, the actions of insulin on the liver, adipose, and skeletal muscle will be the focus of this discussion, although insulin-mediated changes in satiety and blood flow undoubtedly play a role in whole body glucose homeostasis. On binding to its cell surface receptor, insulin elicits a complex cascade of cellular signaling events that have not been elucidated fully to date. This in turn increases glucose transport into the cell (skeletal muscle and adipose), promotes storage of excess carbon from glucose as glycogen (skeletal muscle and liver) and triglyceride (TAG; liver and adipose), increases glucose utilization as a fuel source (skeletal muscle, liver, and adipose), and decreases endogenous glucose production (liver) (see Figure 22-1a). These actions of insulin can be either acute (affecting activity of preexisting proteins) or chronic (altering protein levels).

Skeletal muscle and adipose express two major isoforms of glucose transports, GLUT 1 and GLUT 4. GLUT 1, a ubiquitously expressed glucose

Figure 22-1a. The flow of glucose to tissues under conditions of elevated blood glucose concentration. When [glucose]blood is high, the insulin:glucagon ratio is high, leading to the uptake of glucose into the tissues. Abbreviation: TAG = triacylglycerol

Figure 22-1b. The flow of glucose to tissues under conditions of low blood glucose concentration. When [glucose]blood is low, the insulin:glucagon ratio is low, leading to glycogenolysis and gluconeogenesis in the liver. Abbreviation: TAG = triacylglycerol

transporter, resides almost exclusively at the cell surface, where it facilitates a constant “basal” rate of glucose uptake into the cell. In contrast, GLUT 4, whose expression is limited to skeletal muscle, heart, and adipose, can be found both at the cell surface and within specialized intracellular vesicles. Redistribution of GLUT 4 from intracellular vesicles to the cell surface in response to insulin results in increased rates of glucose transport, thereby facilitating insulin-stimulated glucose disposal. In contrast to skeletal muscle and adipose, the liver expresses GLUT 2. This is a freely reversible glucose transporter that resides permanently at the cell surface. GLUT 2 enables glucose to pass down its concentration gradient, allowing increased hepatic glucose uptake when blood glucose levels are high and increased hepatic glucose efflux when blood glucose levels are low.

Once within the cell, glucose undergoes one of several fates. Insulin promotes incorporation of glucose moieties into glycogen, the storage form of glucose in mammals. This is driven in large part by insulin-mediated activation of protein phosphatase 1 (PP1; Figure 22-2a). PP1 dephosphorylates (hydrolytic removal of regulatory phosphate groups from serine/threonine residues on target enzymes) a number of key proteins involved in glycogen metabolism. Dephosphorylation and activation of glycogen synthase (GS), with a concomitant dephosphorylation and inactivation of glycogen phosphorylase (GP),

Figure 22-2a. Insulin stimulation of the flux of glucose through the glycolytic pathway. Insulin activates protein phosphatase 1, which in turn activates glycogen synthase, phosphofructokinase, and pyruvate kinase. Abbreviations: fructose 1,6-bisphosphate (F1,6BisP); fructose 6-phosphate (F6P); glucose 1-phosphate (G1P); glucose 6-phosphate (G6P); glycogen phosphorylase (GP); glycogen synthase (GS); phosphoenolpyruvate (PEP); phosphofructokinase (PFK); pyruvate kinase (PK); protein phosphatase 1 (PP1)

will stimulate net glycogen synthesis (glycogenesis) by liver and muscle, in response to insulin. One way in which insulin promotes PP1-mediated effects on glycogen metabolism is through the targeting of PP1 to the glycogen particle, a subcellular domain comprised of glycogen itself, as well as the enzymes required for glycogen synthesis and degradation. The glycogen binding subunit is a docking protein allowing PP1 association with the glycogen particle. Insulin induces tyrosine phosphorylation of this glycogen binding subunit, thereby promoting PP1 binding and therefore increased glycogenesis.

The glycogen capacity of a cell is of finite size. Once this capacity is reached, excess glucose must undergo alternative metabolic fates. Insulin promotes flux of glucose through the glycolytic pathway (glucose →2 pyruvate), again in part through PP1 activation (see Fig. 22-2a). As glycogenolysis is the reciprocal pathway to glycogenesis, gluconeogenesis (the synthesis of glucose) is the reciprocal pathway to glycolysis. Gluconeogenesis occurs primarily in the liver and to a lesser extent in the kidney. PP1 increases glycolytic flux in the liver through activation of phosphofructokinase (PFK; indirect effect through dephosphorylation of a bifunctional enzyme, resulting in increased intracellular levels of fructose 2,6-bisphosphate, an allosteric activator of PFK) and pyruvate kinase (PK; direct effect). Glycolytically derived pyruvate could potentially undergo one of two fates in the liver, namely, full oxidation (via Krebs cycle and oxidative phosphorylation) and/or entry into the fatty acid synthesis pathway. However, humans on a Western diet, in which excess calories are more often a mixture of carbohydrate and fat, tend to use ingested carbohydrate as a fuel, while fatty acids are stored as triglyceride in adipose tissue. The latter is driven by insulin.

When blood glucose levels begin to decline (e.g., during an overnight fast), so too does insulin secretion. In contrast, circulating levels of glucagon increase. The latter targets primarily hepatic glucose metabolism in humans, increasing glucose production and decreasing glucose utilization. On binding to its cell surface receptors, glucagon increases the activity of protein kinase A (PKA; Figure 22-2b). In turn, PKA stimulates net glycogen breakdown (glycogenolysis) through phosphorylation of phosphorylase kinase (increases activity) and glycogen synthase (decreases activity). The former phosphorylates and activates glycogen phosphorylase. PKA further antagonizes the effects of insulin through inactivation of PP1. PKA phosphorylates the glycogen binding subunit at specific serine residues, causing the release of PP1 from the glycogen particle. Once released, PP1 binds to inhibitor 1, further inactivating PP1 activity. This PP1-inhibitor 1 association is promoted by PKAmediated phosphorylation of inhibitor 1. Gluconeogenesis is also stimulated

Figure 22-2b. Glucagon promotion of glycogenolysis and gluconeogenesis in the liver. Glucagon binding leads to the activation of protein kinase A, which activates glycogen phosphorylase and fructose-1,6-bisphosphatase, while inhibiting glycogen synthase, pyruvate kinase, and protein phosphatase 1. Abbreviations: protein kinase A (PKA); the rest are the same as in Figure 22-2a.

by glucagon-induced PKA activation, through activation of fructose-1,6- bisphosphatase (F1,6BisPase; indirect effect through phosphorylation of a bifunctional enzyme, resulting in decreased intracellular levels of fructose 2,6- bisphosphate, an allosteric inhibitor of F1,6BisPase) and pyruvate kinase (reverse of PP1 effects). Glycogenolysis- and gluconeogenesis-derived glucose is exported out of the liver to help maintain blood glucose levels.

Abnormalities in the above described glucose homeostatic mechanisms arise during diabetes mellitus. Two major forms of diabetes mellitus exist, insulin-dependent (type I) and non–insulin-dependent (type II) diabetes. Type I diabetes is caused by a severe lack or complete absence of insulin. Also known as early onset diabetes, this disease is often caused by an autoimmune destruction of pancreatic β-cells. In contrast, type II diabetes is caused by insulin resistance in the face of insulin insufficiency. Insulin resistance is defined as an inability to respond to a physiologic concentration of insulin. The pancreas initially compensates by producing more insulin. At this stage, the patient is described as glucose intolerant. As the disease progresses, the degree of insulin resistance often worsens. Type II diabetes occurs when insulin secretion is not sufficient to maintain normoglycemia. The disease is thus characterized by both hyperinsulinemia and hyperglycemia (Figure 22-3).

Figure 22-3. Schematic diagram showing the effects of insulin resistance leading to diabetes mellitus.

The degree at which different organs develop insulin resistance is often not uniform. Skeletal muscle insulin-mediated glucose disposal (which is normally responsible for 60 percent of whole body glucose disposal) is generally more affected, followed next by insulin suppression of hepatic glucose output. The combination of decreased peripheral glucose utilization and increased hepatic glucose production (driven by hepatic insulin resistance as well as increased circulating glucagon levels in type II diabetics) together contribute to the hyperglycemia. Insulin signaling in adipose tissue appears least affected in type II diabetics. Hyperinsulinemia, in the face of hyperglycemia and dyslipidemia (often associated with type II diabetes), drives lipogenesis in adipose tissue and may therefore contribute to the obesity often associated with this disease.

COMPREHENSION QUESTIONS

A 64-year-old man is presented to his family doctor with complaints of frequent episodes of dizziness and of numbness in his legs. During a routine history and physical examination, the doctor finds that the patient leads a sedentary lifestyle, is obese (body mass index of 32), and has hypertension (blood pressure of 200/120 mm Hg). The patient is asked to return to the clinic a week later in the fasting state, during which time a blood specimen is obtained, and a glucose tolerance test is performed. Humoral analysis reveals fasting hyperglycemia, hyperinsulinemia, dyslipidemia, and glucose intolerance. The diagnosis is type II diabetes mellitus.

[22.1] Alterations in substrate metabolism within which of the following organs can be a cause for the observed humoral analysis?

A. Brain

B. Kidney

C. Liver

D. Heart

E. Spleen

[22.2] A mutation, leading to decreased activity, in the gene encoding for which of these proteins is most consistent with this clinical presentation?

A. Glucagon

B. Glucose transporter isoform 1

C. Glycogen phosphorylase

D. Pyruvate carboxylase

E. Protein phosphatase 1

[22.3] Which of the following complications is less likely to occur in type II diabetics, as opposed to type I diabetics?

A. Retinopathy

B. Weight gain

C. Cardiovascular disease

D. Hypoglycemic coma

E. Neuropathy

Answers

[22.1] C. Of the organs listed, changes in hepatic metabolism are most likely to affect circulating glucose and lipids. This in turn influences pancreatic insulin secretion. During type II diabetes mellitus,

increased hepatic glucose output contributes to the observed hyperglycemia and subsequent hyperinsulinemia, whereas complex alterations in lipid metabolism contribute to dyslipidemia. In contrast, changes in metabolic fluxes within the brain, kidney, heart, and spleen are often a consequence, rather than cause, of their environment. For example, the heart increases further reliance on fatty acids as a fuel in the diabetic milieu.

[22.2] E. The underlying cause of type II diabetes mellitus is insulin resistance (an inability to respond normally to physiological concentrations of insulin). Protein phosphatase 1 is an integral mediator of the metabolic effects of insulin. Failure to activate protein phosphatase 1 adequately in response to insulin would therefore attenuate the metabolic actions of this hormone. Decreased activity of glucose transporter 1, glycogen phosphorylase, and pyruvate carboxylase would influence basal glucose transport, glycogenolysis, and gluconeogenesis, respectively. Decreased glucagon levels would tend to improve effectiveness of insulin action.

[22.3] D. Hypoglycemia is a common complication associated with over supplementation of type I diabetics with insulin. This is less common in type II diabetics, because insulin therapy generally occurs only in the later stages of the pathogenesis of this disease. Retinopathy, cardiovascular disease, and neuropathy are common complications associated with both forms of diabetes mellitus. In contrast to type I diabetics, type II diabetics tend to be overweight. Whether weight gain is a cause or consequence of disease progression is under current debate.

BIOCHEMISTRY PEARLS

❖ Serum glucose levels are tightly controlled: Insulin promotes glucose utilization and represses endogenous glucose production, whereas glucagon represses glucose utilization and promotes endogenous glucose production.

❖ Several types of glucose transport proteins appear on specific tissues affecting the movement of glucose across cell membranes.

❖ Glucose is converted into glycogen, the storage form of glucose in mammals, in a process regulated by insulin and insulin-mediated activation of protein phosphatase 1 (PP1).

References

Cohen P. Dissection of the protein phosphorylation cascades involved in insulin and growth factor action. Biochem Soc Trans 1993;21:555. 

Gould GW, Holman GD. The glucose transporter family: structure, function and tissue-specific expression. Biochem J 1993;295:329. 

Newsholme EA, Leech AR. Biochemistry for the Medical Sciences. New York: Wiley, 1983.

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