Metabolic Disorders: Diabetes and Type IV Hyperlipidemia Flashcards
LO #1: Summarize the role of insulin in maintaining blood glucose homeostasis
As discussed in the preceding lecture (see Aerobic Metabolism), insulin plays a critical role in
maintaining the homeostasis of glucose in the blood (see Figure 1) (STEP 1 RELEVANT).
Glucose is the most important energy source. Sources of blood glucose include the diet
(exogenous) in the absorptive phase, liver glycogen (endogenous via glycogenolysis) in the
postabsorptive phase (4-20 h after the last food intake), and de novo glucose synthesis in the
liver in early starvation. Although muscle contains glycogen, this tissue lacks the last enzyme
for synthesizing glucose from glycogen, lactate or amino acids and hence cannot produce
glucose. We previously reviewed the pathways associated with these processes (see
Introduction to Metabolism). Utilization of glucose primarily includes its catabolism,
replenishment of storage pools, and synthesis of fats. The use of glucose in the body diminishes
as food deprivation progresses. Glucose homeostasis is preserved during food deprivation by
certain tissues (e.g., muscle) switching to use of fatty acids during early starvation followed later
by these tissues and brain utilizing ketone bodies in lieu of glucose. Ketone bodies are acids.
When their production is unregulated (e.g., in poorly regulated type 1 diabetes and even in type
2 diabetes mellitus), their concentration becomes excessive causing acidosis. In summary,
insulin acts as an anabolic hormone by increasing the uptake of glucose by muscle and fat cells,
the conversion of glucose to glycogen in liver and muscle, and the production of fatty acids from
glucose in liver and fat cells. As a counter-regulatory hormone, insulin decreases the
mobilization of glycogen (glycogenolysis), inhibits de novo glucose synthesis (gluconeogenesis)
and prevents the excessive mobilization of fatty acids (lipolysis) that can lead to the
development of ketoacidosis.
LO #2: Compare the pathogenesis and clinical features of Type 1 and Type 2 diabetes mellitus
Diabetes mellitus (DM) is not a single disease entity, but rather a group of metabolic disorders
sharing the common underlying feature of hyperglycemia. In 2018, the Burden report provided
the following information about pre-diabetes (metabolic syndrome) and diabetes in Arizona.
[The diabetes data do not distinguish between types 1 and 2, however typically 95% of the
cases are type 2.] In 2014, 9.1% of the population had prediabetes and 10.5% had diabetes.
From 2011-2016, prevalence by race/ethnicity showed American Indians at 18.4%,
Black/African-American at 13.1%, Hispanic at 11.2%, and non-Hispanic white at 9.5%. In the
same period, of those Arizona residents who were obese (BMI>30; 25-29% of the population)
19.7% had diabetes compared to overweight (BMI: 25-29.9; 34-37% of the population) at 9.3%,
and combined normal or underweight (BMI <25; 36-38% of the population) at 7.7%. In other
words, about 80% of the cases of type 2 diabetes are in individuals who are either obese or
overweight. [BMI is calculated as mass (kg)/height (m2
)].
DM results from defects in insulin secretion, insulin action or most commonly, both. Chronic
hyperglycemia and associated metabolic dysregulation may be associated with secondary
organ damage, frequently involving the kidneys, eyes, nerves and blood vessels. DM is the leading cause of end-stage renal disease, adult-onset blindness, and non-traumatic lower
extremity amputation.
LO #3: Explain the laboratory tests and criteria used in the diagnosis of diabetes mellitus
One way to distinguish between Type 1 and Type 2 diabetes early on in these diseases is by
measuring clearance of C-peptide. C-peptide released into the blood together with insulin (see
Protein Synthesis and Structure) is cleared more slowly than is insulin. Consequently, the
concentration of C-peptide can be used to assess the rate of insulin secretion. After an
overnight fast the concentration of C-peptide would be barely detectable, whereas a patient with
an insulinoma would show markedly elevated amounts of C-peptide. Injection of insulin of
course will not generate C-peptide. Type 1 DM is a result of an absolute lack of insulin caused
by a by autoimmune destruction -cells. The lack of C-peptide appearance after a meal would
be a clear indicator that the individual has type 1 DM though notably as type 2 DM progresses
(see below) secretion of insulin and hence of C-peptide can decline markedly.
LO #4: Interpret how metabolic syndrome is key to development of type 2 diabetes mellitus, the
significance of metabolic susceptibility in this development and a medication that might be
prescribed to treat the syndrome
Appreciable evidence indicates that obesity precedes the development of metabolic changes
leading to type 2 DM. A broad definition of metabolic syndrome is a “cluster of biochemical and
physiological abnormalities associated with development of cardiovascular disease and type 2
DM.” Waist circumference may be a predictor of metabolic syndrome incidence and by
association, the likelihood of the individual developing type 2 diabetes. Large waist
circumference is defined by the National Institutes of Health as greater than 35 inches for
women and 40 inches for men. The prevalence of metabolic syndrome is high among obese
children and teens, and that incidence increases with worsening obesity. Metabolic syndrome
may also be referred to as insulin resistance syndrome or syndrome X. For a somewhat recent
UpToDate summary see Patient education: The metabolic syndrome (Beyond the Basics); JB
Meigs; literature review current through Sep 2018; topic last updated Nov 21, 2017; Topic 2183
Version 21.0.
Simply having excess fat does not necessarily lead to the metabolic syndrome, unless the
individual is also metabolically susceptible to the syndrome. Metabolic susceptibility may
include factors such as defects in insulin signaling, disorders of adipose tissue metabolism,
sedentary lifestyle, and other variables. Metabolic susceptibility may explain why 20% of
patients with type 2 DM are not overweight. The bottom line is that individuals who have some
or multiple forms of metabolic susceptibility likely will develop the syndrome when excess body
fat compounds the situation. Many individuals with metabolic susceptibility may exhibit insulin
resistance as well which is why some refer to the metabolic syndrome as the insulin resistance
syndrome. By avoiding adding excess fat, those with metabolic susceptibility are less likely to
ever develop the syndrome. The syndrome is characterized by a progression of changes in
metabolism that can be tied to several adipose tissue products that are cytokines.
LO #5: Discuss the medications that are used in the treatment of type 2 DM, the mechanisms of
action of each medication, and discuss how this treatment would differ for type 1 DM
As T2DM progresses, the ability of the pancreatic -cells to produce insulin may diminish.
Sulfonylureas are medications that aid patients with diabetes who have sluggish insulin
release. The first generation sulfonylureas included tolbutamide and chlorpropamide. The second-generation group include glimepiride, glyburide, and glipizide. These drugs mimic ATP
effects by binding to receptors that close potassium channels and thereby allow calcium to enter
and stimulate insulin release (Figure 2). Meglitinides (e.g., repaglinide) also stimulate the
pancreas to produce more insulin similar to sulfonylureas but bind to a different site.
An exogenous source of insulin is required for patients with type 1 DM because synthesis of
insulin no longer occurs. Several analogs of human insulin have been developed (Table 4).
They produce the typical anabolic effects on metabolism including increased storage of glucose
as glycogen in liver and muscle, increased storage of triglycerides in fat cells, increased muscle
protein synthesis and increased cellular uptake of potassium. Clinically they are used in
treatment of type 1 DM but also are used in treatment of patients with type 2 DM who have
decreased insulin secretion (see above).
Rapid acting (1 h peak) insulin preparations include Lispro, Aspart and Glulisine. Regular
human insulin is considered a short-acting type (2-3 h peak) and provides postprandial glucose
control as well as being used intravenously in the treatment of diabetic ketoacidosis (DKA).
Additionally, this form can be used in patients with hyperkalemia or stress-induced
hyperglycemia. NPH is an intermediate-acting form with a 4 to 10 h peak. Glargine and
Detemir are both long acting with no real peak and used to maintain basal glucose control.
LO #6: Discuss the nature of type IV hyperlipidemia as it pertains to obesity and poorly controlled
type 2 diabetes and the medications used in treating this disease.
Fatty acids synthesized in the liver from excess dietary glucose are stored as triglyceride.
Dietary saturated fatty acids are converted to cholesterol in the liver. Both of these lipid
components are secreted by the liver so that they can be delivered to other tissues for utilization
or storage. Triglycerides primarily go to adipose tissue where the fatty acids are hydrolyzed from
the glycerol backbone and then reassembled in the fat cells as triglyceride. Cholesterol is
delivered to a wide variety of cells as it is an important component of cell membranes.
Additionally, cholesterol is used for the production of steroid hormones in several endocrine
producing cells and for synthesis of vitamin D in the skin. The triglycerides together with cholesterol are packaged in very-low-density lipoproteins (VLDL) particles that are
assembled in the liver (Figure 8). After processing at fat and muscle cells, the particle loses
most of its triglycerides leaving mostly cholesterol in the modified particle that is now a lowdensity lipoprotein (LDL) that delivers the cholesterol. When excess VLDL accumulates in the
circulation a condition develops called hyperlipidemia and more specifically
hypertriglyceridemia to reflect the elevated triglycerides in the circulation. There are five types of hyperlipidemias. Type IV accounts for about 45% of the cases with a
frequency of approximately 1:100. Unlike the other types of hyperlipidemia that are inherited
(i.e., congenital), type IV is not inherited and therefore is considered` an acquired disease. Type
IV is also referred to as familial hypertriglyceridemia. A primary characteristic of the disease is
increases in triglycerides due to elevated production of VLDL and its decreased elimination. In
contrast, blood cholesterol concentration tends to be normal. The normal concentration of
triglycerides in the blood should be below 150 mg/dL with 150-199 mg/dL being considered
borderline high and 200 or more is abnormally high. Patients with type IV hyperlipidemia have
blood concentrations over 200 mg/dL but less than 1000 mg/dL. VLDL concentrations are increased because of overproduction by the liver, often due to obesity, poorly controlled
diabetes mellitus or alcohol abuse. Genetics may play a role in the propensity for developing
type IV hyperlipidemia. Because of insulin resistance, patients with type 2 DM cannot easily
inactivate the enzyme that releases fatty acids from triglyceride (i.e., hormone sensitive lipase).
Without insulin action to counter-regulate its effects, glucagon is unopposed in stimulating this
enzyme resulting in the mobilization of fatty acids from adipose cells. Albumin in the blood
carries these fatty acids which to the liver. The liver re-esterifies these fatty acids into
triglycerides, which are then exported in VLDL into the circulation. Obesity is usually a
consequence of excessive intake of dietary carbohydrates that are converted to fatty acids in
the liver. As a consequence, severe hypertriglyceridemia can occur. The incidence of hardening
of the arteries increases in these patients putting them at risk for various heart conditions
including coronary artery disease.
Management: Not surprisingly the goal of treatment is regulating those factors that elevate
serum TAGs. Some medications such as estrogen can contribute to elevated TAGs.
Medications used to treat these patients include gemfibrozil, which belongs to a group of
medications known as fibrates. Fish oils contain omega-3-fatty acids that also can lower
circulating triglycerides. A prescription grade of omega-3-fatty acids is available as lovaza
