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Home / Resources / Clinical Gems / Joslin’s Diabetes Deskbook, Updated 2nd Ed., Excerpt #40: Multiple Treatments for a Multicomponent Condition, Part 1

Joslin’s Diabetes Deskbook, Updated 2nd Ed., Excerpt #40: Multiple Treatments for a Multicomponent Condition, Part 1

Please note that the source for this excerpt was misidentified on our initial publication. We have since corrected this mistake with the correct attribution.

Richard S. Beaser, MD

Joslin_Diabetes_Deskbook

Introduction 

The current term "type 2 diabetes" represents an evolution in terminology reflecting a progression in the understanding of this condition. The change to the Arabic numeral "2" from the Roman numeral "II" is only the latest in the evolution of descriptive terminology. This type of diabetes was previously known as non-insulin-dependent diabetes; maturity onset diabetes, and adult-onset diabetes. Unfortunately, some people even called it "borderline" diabetes when insulin was not needed as therapy….

The change in terminology, while intended to eliminate confusion implied by the previous names, also reflects the varied pathophysiology, patient demographics, and treatment for this condition. People with type 2 diabetes may be both insulin treated and non-adult. And it is far from the trivial abnormality that the term "borderline" implies. Even when the glucose abnormalities are seemingly minimal, the potential impact on health can be significant.

Type 2 diabetes is by far the most common type of diabetes, representing close to 95% of all people with this condition. Unfortunately, too, it is probably more common than people realize. Its onset is often minimally symptomatic, and thus the insidious development of this condition often goes unrecognized for many years. Estimates have suggested that one-third of all people who actually have this condition do not yet know it. Yet, ignorance is not bliss. The hyperglycemia, as well as the other components of the cardiometabolic syndrome (also referred to as the insulin resistance syndrome), of which type 2 diabetes is a part, are silently impacting the vasculature, with significant long-term implications for morbidity and mortality. While predominantly an adult disease, type 2 diabetes is becoming more prevalent among children and adolescents.

Insulin Resistance 

As explained above, type 2 diabetes is usually part of a spectrum of abnormalities often referred to as the cardiometabolic syndrome. The pathophysiologic hallmark of this condition is insulin resistance, manifest in liver and peripheral (primarily muscle and adipose) tissue. When insulin resistance is present, more insulin is required to produce a given degree of glucose-lowering effect. However, for type 2 diabetes to be present, there needs to be dual defects: the insulin resistance and a relative or absolute insulin secretory insufficiency so that there is not enough insulin produced to overcome the insulin resistance.

Insulin resistance is not always accompanied by type 2 diabetes. In fact, insulin resistance may be present, but with other clinical manifestations such as dyslipidemia and/or hypertension. If the pancreas is capable of making enough additional insulin to overcome the insulin resistance and maintain normal glucose tolerance, there is no hyperglycemia or clinical manifestation of diabetes. This is usually the case in early stages of type 2 diabetes. However, as the insulin resistance causes the body to need increased amounts of insulin, when the pancreas is able to respond by producing this additional insulin output, the person is said to have become hyperinsulinemic. Hyperinsulinemia is associatedwith many of the other macrovascular risk factors that make up the metabolic syndrome, including dyslipidemia and hypertension. The exact etiologic relationship between the hyperinsulinemia and the development of these other conditions is not fully understood. However, many people believe that the hyperinsulinemia represents a marker for the syndrome rather than a cause of the risk factors in question.

Insulin resistance can be found in both the liver and peripheral tissues. With insulin resistance and insufficient compensatory hyperinsulinemia, increased hepatic glucose production occurs. This production is most often reflected clinically in elevations of fasting glucose levels. When the fasting glucose level rises to above 100 mg/dl, it is classified as impaired fasting glucose, and when it rises to 126 mg/dl or above, diabetes is diagnosed.

Peripheral insulin resistance is usually due to a number of defects, including post-insulin receptor binding defects, leading to decreased glucose transport and metabolism.

The Pathophysiology and Natural History of Type 2 Diabetes

For a number of years prior to the clinical manifestation of hyperglycemia, many people who will develop type 2 diabetes have an insidious increase in insulin resistance. During this time, the pancreas will increase insulin output, and normoglycemia is maintained.

However, for many people destined to develop type 2 diabetes, the ability of the pancreas to secrete enough additional insulin may decline. This decline may actually begin as many as 10 years prior to diagnosis of diabetes. It is usually a decrease in the early, or first phase, insulin secretion that occurs while second phase insulin secretion is increased. Concurrently, there is also a reduced suppression of glucagon in the postprandial state, which leads to increases in endogenous glucose production, further contributing to postprandial hyperglycemia.

When the insulin secretory capacity is significant enough to overcome the insulin resistance, normoglycemia is maintained. However, if that excess secretory capacity begins to wane, mild hyperglycemia may develop. If one compared this person’s level of insulin secretion to that of someone without diabetes and with normal glucose levels, the insulin level would be elevated. However, in spite of this elevated insulin level, β-cell function is insufficient to overcome the insulin resistance. Thus, we say that this individual has a relative insufficiency of insulin secretory capacity and is unable to overcome insulin resistance. By the time clinical diabetes is diagnosed, more than 50% to 75% of â-cell function is lost.

It is at this time, when mild hyperglycemia develops, that diabetes should be diagnosed, but the lack of symptoms often leads to delays in disease discovery. Making the diagnosis earlier — at this stage in the progression — may be the best time to intervene with lifestyle changes that will prevent type 2 diabetes, as well as vascular disease, from progressing. In the Diabetes Prevention Program, intervening at the stage of impaired glucose tolerance with lifestyle changes resulted in a 58% reduction in diabetes progression as well as a 9% reduction in the number of persons with metabolic syndrome.

At the time that diabetes is diagnosed, there are a number of abnormalities in physiology that are likely to be present. Initially, the insulin resistance is more peripheral — muscle and adipose — reflecting decreases in postprandial glucose uptake. In addition, at the level of the beta-cell, there is a loss of first-phase insulin release. Normally, insulin is released in two phases. The first phase represents pre-made insulin within the beta-cell, and is released in the first 15 minutes after carbohydrate intake commences.

It prevents a sharp rise in glucose levels in the immediate postprandial period. The second phase of insulin release represents newly manufactured insulin and begins as the first phase is subsiding. It lasts longer and provides sustained carbohydrate coverage for the remainder of the incoming nutrients.

With the loss of the first phase of insulin release, the postprandial glucose level often rises significantly. Also contributing to this is the lack of glucagon suppression, which further promotes production of endogenous glucose. However, as these people retain their second-phase release, the higher postprandial glucose level leads to a greater amount of insulin produced during this period. For some people at this stage, a pattern of reactive hypoglycemia may be seen. This happens because muscle is the main source of glucose uptake after meals and more insulin is needed to drive glucose into muscle cells than fat cells or to suppress the liver output of glucose. The higher insulin levels can lead to a drop in blood glucose 3 to 5 hours after a meal and symptoms of hypoglycemia may occur.

In addition, as the glucose level begins to rise, glucose toxicity can develop. Glucose toxicity is the paradoxical effect of hyperglycemia on insulin production and insulin action. Rather than driving the pancreas to make more insulin and the cells to be more insulin responsive, just the opposite occurs. Insulin secretory capacity is blunted, glucagon levels are elevated, and insulin resistance increases. Thus, there can be a vicious-cycle effect: the initial mild hyperglycemia can worsen beta-cell function and insulin sensitivity, leading to more hyperglycemia and more decreases in and insulin sensitivity. With time, more significant hyperglycemia can develop. Even fasting hyperglycemia that is minimally above normal levels can contribute to glucose toxicity and blunt first phase insulin response.

Once hyperglycemia begins to develop, the degree of insulin resistance often plateaus. From that point on, most people maintain a static degree of insulin resistance, only varying as a result of external forces such as significant changes in food intake and activity level, physiologic stress, glucose toxicity, or glucose-sensitizing medications. The further progression of the disease is, from this point on, driven primarily by the decline in β-cell function.

During this period of time, glucose patterns, assessed from reviewing the person’s self-monitoring of blood glucose (SMBG) records, can reflect the progressive deterioration in insulin secretory capacity. From the initial abnormalities in postprandial glucose levels seen with the early stages of β-cell dysfunction, more significant pre-and postprandial glucose elevations can result. Fasting glucose levels can be more significantly elevated than those before lunch and supper, resulting from multiple factors such as the hyperglycemia of the dawn phenomenon, the lack of eating to stimulate insulin secretion increasing hepatic insulin resistance and decreasing insulin secretion. Fasting insulin levels are often elevated, yet still insufficient to normalize glucose levels. When preprandial, and particularly fasting, glucose levels remain under 200 mg/dl and A1C values under about 9%, non-insulin antidiabetes treatments (oral and/or injectable exenatide) can often provide adequate glucose control early in the course of the disease, targeting pre- and post-prandial hyperglycemia.

With progressive decrease of insulin capacity, glucose levels rise further and often herald the approaching need for exogenous insulin. The longer the duration of diabetes in these instances, the more likely that exogenous insulin therapy will be needed. Specific insulin treatment options are discussed in more detail in Chapters 10 and 11.

Over time, decreases in insulin secretory capacity can be reflected in evolving changes in glucose patterns which can suggest the pathophysiologic progression of this condition:

  • Rising glucose levels during the day — In early stages of type 2 diabetes, the prebreakfast glucose levels are typically higher than values before lunch and supper. As insulin secretory deficiency progresses, the prelunch and presupper values rise, so that the fasting glucose is not notably higher than these later premeal values. This is one reflection of declining insulin secretory capacity.
  • Marked postprandial hyperglycemia — Another reflection of a decline in insulin secretory capacity — the decline of second phase secretion—is a more marked difference between pre-and postprandial glucose levels. Loss of first-phase insulin response can cause postprandial hyperglycemia early-on in the natural history of this condition, but a more pronounced postprandial rise reflects more significant second-phase insufficiency. A rising A1C with significant postprandial hyperglycemia would signal a need to target this time period with therapeutic interventions, including insulin.
  • Marked hyperglycemia throughout the day — reflects further insulin secretory deficiency. Fasting glucose is elevated, and there are further elevations in values before lunch and supper. At this point, prandial coverage is insufficient and basal insulin also cannot return glucose values to baseline. Exogenous insulin therapy is almost certainly needed when glucose patterns reach this stage, particularly in the setting of a rising A1C and the use already of multiple antidiabetes medications.
  • General lability in response to daily activities — reflects even further deterioration in insulin secretory capacity and glucose homeostatic mechanisms. In all likelihood, when such instability in patterns is seen, insulin production levels have dropped to an absolute deficiency. Physiologic insulin replacement programs similar to those used to treat people with type 1 diabetes are recommended at this stage.
Treatment Goals 

The goal of treating any type of diabetes can be summarized as being the prevention of its acute and chronic complications.As this applies to type 2 diabetes, the objectives really represent a more comprehensive approach to reducing macrovascular risk and include:

  • Glucose control. Achieving this objective prevents acute complications of hypo-and hyperglycemia and, based on recent study data, reduces the risk of microvascular and neuropathic complications and contributes to reducing the risk of macrovascular complications. The EDIC study, which was a follow up of the DCCT Study, recently showed the importance of physiologic early glycemic control with type 1 diabetes. Subjects in the intensive treatment group whose control deteriorated after the main study, still had less progression in their microvascular disease compared to the standard treatment subjects who had the higher A1C during the trial and whose control was now improved. Thus early tight glycemic control in these people with type 1 diabetes had a legacy effect on the vascular tissues. In addition, the physiologic glucose control also reduced the risk of macrovascular disease for the first time. Similar data has been reported from the follow up of the UKPDS among people with type 2 diabetes.
  • Reduction of cardiovascular risk factors and cardiovascular complications. These include clinically targeting dyslipidemia, hypertension, hypercoagulability, obesity, vascular dysfunction, inactivity, and cigarette smoking. However, the question of how tight glucose control should be with respect to its impact on reduction in cardiovascular disease is still not answered. The much anticipated ACCORD, VADT and ADVANCE trials were inconclusive in this regard, and have led to some discussion as to whether we should slightly loosen our glycemic targets in people with longer-duration type 2 diabetes and coronary artery disease. (See Chapter 8 for a further discussion of this issue.) For others, aggressive control may still be appropriate, but in addition, concurrently addressing the other components of the cardiometabolic syndrome (hypertension, dyslipidemia, weight management) is also important.Prevention of other complications, including microvascular and neuropathic effects, by addressing issues such as treatment of microalbuminuria, regular ophthalmologic evaluations, and proper foot care. Interventions to achieve these goals are discussed in detail in other chapters devoted to the specific topics. However, specific considerations as these issues apply to people with type 2 diabetes are outlined next in Part 2 in 2 weeks.

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