Access Medicine Clinical Rotation Cases Files Basic Science/Biochemistry, Case Study - Type 2 Diabetes

Discipline: Nursing

Type of Paper: Question-Answer

Academic Level: Undergrad. (yrs 3-4)

Paper Format: APA

Pages: 4 Words: 1000


A 50-year-old Hispanic woman presents to your clinic with complaints of excessive thirst, fluid intake, and urination. She denies any symptoms of urinary tract infection and reports no medical problems; however, she has not seen a doctor in many years. On examination, she is an obese woman in no acute distress. Her physical examination is otherwise normal. Urinalysis revealed 4+ 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 2 Diabetes

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

  • Diagnosis: Type 2 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 when 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 2 types depending on the pathogenesis. Type 1 diabetes is characterized by insulin deficiency and usually has its onset during childhood or teenage years. This is also called ketosis-prone diabetes. Type 2 diabetes is caused by insulin resistance and usually has elevated insulin levels, and it is diagnosed in the adult years. Type 2 diabetes is far more common than type 1 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. In addition, 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.


  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.


DIABETES MELLITUS: An endocrine disease characterized by an elevated blood glucose concentration. There are 2 major forms of diabetes mellitus: type 1, or insulin-dependent, and type 2, or non–insulin-dependent. Type 1 is caused by a severe lack or complete absence of insulin. Type 2 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 (PFK-2)/fructose bisphosphatase-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 cyclic adenosine monophosphate (cAMP) concentration in the cell that is a response to the activation of adenylate cyclase by binding of certain hormones on cell surfaces.


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 (eg, erythrocytes). Neurons, although can use alternative fuel sources under extreme conditions (eg, ketone bodies during prolonged starvation), have a strong preference toward glucose utilization. Therefore, circulating levels of glucose must be maintained sufficiently high to meet the energy demands of the body. Chronic elevations in blood glucose levels are also detrimental, because they are 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 in cases of 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). By 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). Therefore, a careful balance between the actions of insulin and glucagon helps maintain blood glucose levels within a normal range.

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. 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. TAG = triacylglycerol.

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 2 major isoforms of glucose transports, GLUT 1 and GLUT 4. GLUT 1, a ubiquitously expressed glucose transporter, resides almost exclusively at the cell surface, where it facilitates a constant “basal” rate of glucose uptake into the cell. By 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. By 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), 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.

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. 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.

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), in part through PP1 activation (see Figure 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 1 of 2 fates in the liver, namely, full oxidation (via the Krebs cycle and oxidative phosphorylation), entry into the fatty acid synthesis pathway, or both. 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 (eg, during an overnight fast), so too does insulin secretion. By 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, thus further inactivating PP1 activity. This PP1-inhibitor 1 association is promoted by PKA-mediated phosphorylation of inhibitor 1. Gluconeogenesis is also stimulated 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.

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. 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, PKA = protein kinase A, protein phosphatase 1 = PP1.

Abnormalities in the above described glucose homeostatic mechanisms arise during diabetes mellitus. 2 major forms of diabetes mellitus exist, insulin-dependent (type 1) and non–insulin-dependent (type 2) diabetes. Type 1 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 2 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 2 diabetes occurs when insulin secretion is not sufficient to maintain normoglycemia. The disease is thus characterized by both hyperinsulinemia and hyperglycemia (Figure 22-3). 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% 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 people with type 2 diabetes) together contribute to the hyperglycemia. Insulin signaling in adipose tissue appears least affected in people with type 2 diabetes. Hyperinsulinemia, in the face of hyperglycemia and dyslipidemia (often associated with type 2 diabetes), drives lipogenesis in adipose tissue and may therefore contribute to the obesity often associated with this disease.

Figure 22–3.

Schematic diagram showing the effects of insulin resistance leading to diabetes mellitus.


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 PP1.


Cohen  P. Dissection of the protein phosphorylation cascades involved in insulin and growth factor action. Biochem Soc Trans. 1993;213:555–567.
[PubMed: 8224471]

Gould  GW, Holman  GD. The glucose transporter family: structure, function and tissue-specific expression. Biochem J. 1993;2952:329–341.
[PubMed: 8240230]

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

Question 1 of 3


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 kg/m2), and has hypertension (blood pressure of 200/120 mm Hg). The patient is asked to return to the clinic 1 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 2 diabetes mellitus.

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











You will be able to view all answers at the end of your quiz.

The correct answer is D. You answered D.


D 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 2 diabetes mellitus, increased hepatic glucose output contributes to the observed hyperglycemia and subsequent hyperinsulinemia, whereas complex alterations in lipid metabolism contribute to dyslipidemia. By 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.


Question 2 of 3


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




Glucose transporter isoform 1




Pyruvate carboxylase



You will be able to view all answers at the end of your quiz.

The correct answer is E. You answered E.


E The underlying cause of type 2 diabetes mellitus is insulin resistance (an inability to respond normally to physiologic concentrations of insulin). PP1 is an integral mediator of the metabolic effects of insulin. Failure to activate PP1 adequately in response to insulin would therefore attenuate the metabolic actions of this hormone. Decreased activity of glucose transporter 1, GP, and pyruvate carboxylase would influence basal glucose transport, glycogenolysis, and gluconeogenesis, respectively. Decreased glucagon levels would tend to improve effectiveness of insulin action.


Question 3 of 3


Which of the following complications is less likely to occur in people with type 2 diabetes compared with those with type 1 diabetes?




Weight gain


Cardiovascular disease


Hypoglycemic coma



You will be able to view all answers at the end of your quiz.

The correct answer is D. You answered D.


D Hypoglycemia is a common complication associated with over supplementation of people with type 1 diabetes taking insulin. This is less common in people with type 2 diabetes, 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. By contrast to type 1 diabetes, patients with type 2 diabetes tend to be overweight. Whether weight gain is a cause or consequence of disease progression is under current debate.