Hypoglycemia
Hypoglycemia is a more common emergency than DKA and potentially as dangerous. Clinical hypoglycemia can range from annoying symptoms accompanying a biochemically low blood glucose level (< 50 to 60 mg/dl) to confusion, seizures, or coma. Any episode that requires intervention by another person to reverse is categorized as severe hypoglycemia. Severe hypo-glycemia can have disastrous consequences, particularly if the patient is driving any sort of vehicle, working at heights, or operating potentially dangerous machinery.
The most common causes of hypoglycemia are missed meals and snacks,117 insulin dosage errors, exercise, alcohol, and drugs such as beta-adrenergic blockers. During the DCCT, 55% of hy-poglycemic episodes occurred during sleep.117 Such episodes often go undetected.
Glucagon and epinephrine are the major counterregulatory hormones that are secreted in response to hypoglycemia.119 Both restore glucose levels by increasing hepatic glucose output, while epinephrine also decreases the sensitivity of muscles to insulin. Furthermore, catecholamine secretion alerts the patient to treat the episode because it produces the sympathoadrenal symptoms noted below. Cortisol and growth hormone are also secreted in response to hypoglycemia119 and play a role in maintaining glucose levels but not in rapid recovery from hypoglycemia.
Presenting features The most common symptoms of early mild hypoglycemia are adrenergic and include tachycardia, tremulousness, anxiety, and sweating.120 The last symptom requires sympathetic activation of cholinergic nerves innervating the sweat glands.
Factors affecting severity of hypoglycemic episodes The development of primary or secondary adrenal insufficiency, hy-popituitarism, and hypothyroidism may increase the risk of hypoglycemia by increasing sensitivity to insulin, decreasing appetite, or both. Stress, exercise, or use of alcohol or illicit drugs may blunt or prevent recognition of hypoglycemia. Patients who do recognize incipient hypoglycemia but who consciously do not respond expeditiously (for example, they may wait for a meal in a restaurant or continue to drive after symptoms first appear) are also at increased risk for severe hypoglycemia. Moreover, some risk factors for hypoglycemia have multiple effects that can precipitate, prolong, or worsen the severity of hypoglycemia. Alcohol, for instance, impairs judgment and inhibits gluconeogenesis and hepatic glucose output, thereby delaying recovery. When hypoglycemia is inadequately treated, more severe hypo-glycemia often ensues.
Finally, because glucagon and epinephrine are the major defense hormones against prolonged hypoglycemia, their absence promotes longer and more severe episodes by two mechanisms: (1) compensatory hepatic glucose output is decreased when not stimulated by glucagon or epinephrine and (2) the familiar adren-ergic symptoms may cease in the absence of epinephrine, resulting in failure to recognize the episode.119 The glucagon response to hypoglycemia often wanes in patients after they have had type 1 diabetes mellitus for a few years. In the absence of glucagon, epi-nephrine secretion still provides adequate counterregulatory defense; however, epinephrine response can also be lost eventually, sometimes in association with other autonomic neuropathies and sometimes selectively. Many patients lose the ability to counterregulate against hypoglycemia during the first 10 years that they have type 1 diabetes mellitus.
Given the importance of intensive regimens to prevent mi-crovascular complications from hyperglycemia, it is most unfortunate that a lowered glucose threshold for release of glucagon and epinephrine in response to hypoglycemia has been observed, particularly in patients undergoing intensive insulin therapy.121 The lowered glucose level needed to stimulate counterregulation narrows the safety margin of therapy. For instance, the first symptom of hypoglycemia may occur only at glucose levels as low as 35 mg/dl (as opposed to 55 to 60 mg/dl) and may consist of confusion or loss of judgment, which interferes with self-treatment. Some evidence suggests that unawareness of hypogly-cemia is self-generating, because each episode may lower the threshold at which autonomic counterregulation begins in subsequent episodes.119 The converse of this is that a period free of hypoglycemia, produced by daily therapeutic contact with care-givers, may restore hypoglycemia awareness,122,123 though it may not restore normal counterregulatory responses.122 Increased uptake of glucose by the brain in the presence of hypoglycemia124,125 is a likely explanation for the relative infrequency of clinical hy-poglycemic catastrophes.
Treatment Patients recognize most episodes of hypo-glycemia quickly and can effectively treat themselves with a promptly absorbed oral carbohydrate. Approximately 15 g of carbohydrate is sufficient to restore blood glucose levels to normal. This amount is provided by approximately 6 oz of orange juice, 4 oz of a cola drink, 3 to 4 tsp of table sugar, five Life Savers, or three glucose tablets (each containing 5 g of glucose). The use of complex carbohydrates and foods with a high fat content, such as chocolate, may delay digestion and absorption of the glucose and are not first choices for treatment of hypoglycemia. If the patient cannot swallow or cooperate, a gel form of glucose and simple carbohydrates can be administered by mouth, applying it between the gums and cheeks, from where it slowly and generally safely trickles down into the stomach. Glucagon (1 mg administered subcutaneously or intramuscularly) will also usually raise blood glucose levels sufficiently within 15 to 30 minutes, when the patient can then take oral carbohydrates. Glucagon comes in emergency kits, and it should always be on hand for patients with a history of severe hypoglycemic episodes. Glucagon may cause nausea, vomiting, and headache, especially in children. When all else fails, intravenous glucose must be given by emergency medical service personnel or in an emergency room, whichever is quicker. When the timing of an episode suggests it was caused by intermediate- or long-acting insulin or by prior exercise, blood glucose may fall to hypoglycemic levels again and re-treatment may be necessary. Thus, a patient who has required assistance from others in reversing hypoglycemia should be kept under surveillance for some time thereafter.
Figure 14 (a) The interrelations of insulin resistance, insulin deficiency, and glucose toxicity that create overall hyperglycemia in type 2 diabetes mellitus are depicted. Insulin resistance and insulin deficiency are mutually reinforcing factors. Glucose toxicity refers to the secondary aggravating effects of hyperglycemia that both increase insulin resistance and reduce beta cell function. The glucose toxicity is diminished or eliminated by any therapy that lowers blood glucose. (b) Once fasting glucose levels are abnormal, they are correlated with and largely driven by the excess hepatic glucose production. Abnormal postprandial glucose levels are largely a consequence of peripheral insulin resistance that makes glucose utilization in muscle and adipose tissue inefficient. Insulin deficiency plays an increasingly important role in elevating both fasting and postprandial glucose levels as time goes on.
Patients with severe hypoglycemia usually respond rapidly to treatment, although patients who are postictal or in a prolonged coma may require days to regain normal mental status and cognitive function. Quite often, there is amnesia for such extended episodes, including a period preceding the onset of hypo-glycemia. In rare instances, neurologic deficits can be permanent. In general, however, long-term consequences of hypoglycemia have not been detected in adults.126,127 In view of the potential consequences of prolonged episodes, hypoglycemia should always be treated immediately.
Prevention Patients should be instructed to treat themselves as though they have hypoglycemia whenever they suspect it, even if they are unable to do a confirmatory blood glucose test at the time. The threshold for symptoms of hypoglycemia varies from person to person and even varies in the same person on different occasions. Therefore, whenever possible, a confirmatory blood glucose test should be done to help the patient discriminate nonspecific symptoms from true hypoglycemia. Patients at increased risk for severe hypoglycemia should monitor their blood glucose levels more frequently.
Type 2 Diabetes Mellitus
Pathogenesis of type 2 diabetes mellitus
Insulin Resistance and Insulin Deficiency
The pathogenesis of type 2 diabetes mellitus128 is even more complex than that of type 1 diabetes mellitus. Insulin resistance, reported in 92% of one large group of people with type 2 diabetes mellitus,129 plays a major role in generating hyperglycemia.128 In addition, some degree of functional insulin deficiency exists [see Figure 14].128 Certain studies suggest that insulin resistance is pri-mary128,130 and that impaired insulin secretion is only really evident when fasting hyperglycemia supervenes.128, 131-133 Other investigators find evidence of early abnormal beta cell function in type 2 diabetes mellitus,134-136 in IGT,134,137 and in first-degree glucose-tolerant relatives of patients with type 2 diabetes mellitus.138 Regardless of which comes first, the loss of compensatory beta cell hy-perfunction to overcome insulin resistance is a key factor in the progression from genetic susceptibility to established type 2 diabetes mellitus.139 Furthermore, insulin resistance may cause secondary insulin deficiency, and insulin deficiency tends to lead to insulin resistance; thus, they are mutually reinforcing defects, partly through an effect commonly referred to as glucose toxici-ty.140 Some period of hyperglycemia has a secondary noxious effect that aggravates both insulin resistance and insulin deficiency; thus, hyperglycemia begets hyperglycemia. Therefore, any form of treatment of type 2 diabetes mellitus that lowers plasma glucose levels is self-reinforcing and may gain momentum with time by virtue of the added early benefit of eliminating the effects of glucose toxicity. For this reason, aggressive early treatment (e.g., with insulin) can sometimes be replaced with oral drugs or even diet.
The exact locus of insulin resistance in type 2 diabetes mellitus remains unidentified. Indeed, there may be various sites because the disease is considered likely to be a heterogeneous disor-der.142,143 Numerous candidate genes for defective insulin action, including the insulin receptor, glucose transporter, insulin receptor substrate, and insulin target enzymes, such as glycogen syn-thase, have been largely excluded as common primary causes of insulin resistance144,145 in type 2 diabetes mellitus.
As in type 1 diabetes mellitus, the loss of effective insulin action directly leads to unrestrained hepatic glucose production and inefficient peripheral glucose utilization [see Figure 14]. Excessive hepatic glucose output largely accounts for elevation of FPG levels.128 Resistance to the antilipolytic action of insulin in adipose tissue leads to elevated plasma free fatty acid (FFA) levels and increased FFA delivery to the liver. There, the oxidation of FFA generates energy (adenosine triphosphate [ATP]) needed to sustain gluconeogenesis; in addition, the latter process is stimulated by FFA metabolites such as acyl coenzyme A (acyl-CoA). In this indirect manner, insulin resistance also contributes to elevated glucose production in the liver.146 Moreover, the elevation of FFA levels also contributes to insulin resistance in muscle.147 The presence of some residual insulin secretion in type 2 diabetes mellitus, however, is ordinarily enough to restrain ketogenesis and prevent DKA. Elevated hepatic glucose output largely sustains an elevated FPG, whereas reduced peripheral glucose utilization especially causes elevation of postprandial glucose levels [see Figure 14].
Table 6 Definitions of the Metabolic Syndrome155,156
|
National Cholesterol Education Program Adult Treatment Panel III |
World Health Organization |
|
At least three of the following: |
Diabetes, IGT, or IFG and/or insulin resistance* plus at least two of the following: |
|
Fasting plasma glucose > 110 mg/dl |
|
|
Abdominal obesity: waist circumference 35 in. in women or > 40 in. in men |
Abdominal obesity: waist-to-hip ratio > 0.85 in women or > 0.9 in men and/or body mass index > 30 kg/m2 |
|
< 50 mg/dl in women or < 40 mg/dl in men |
Triglycerides > 150 mg/dl and/or HDL < 40 mg/dl in women or < 35 mg/dl in men |
|
Blood pressure > 130/85 mm Hg |
|
|
Blood pressure > 140/90 mm Hg |
|
|
Microalbuminuria: urinary albumin excretion > 20 |g/min or albumin-to-creatinine ratio > 30 mg/g |
*Insulin resistance assessed as fasting insulin ^ (fasting glucose x 22.5).
HDL—high density lipoprotein
IFG—impaired fasting glucose
IGT—impaired glucose tolerance
The ratio of proinsulin to insulin in plasma is high and remains so even after glucose-lowering therapy,148,149 suggesting an early abnormality in processing of proinsulin to insulin in the beta cell [see Figure 3]. Insulin is normally secreted in cyclic pulses that can be entrained by rapid changes in plasma glucose levels. Disruption of this close concordance between plasma glucose and plasma insulin fluctuations is a subtle lesion that is demonstrable early in patients with type 2 diabetes mellitus and, to a lesser extent, in some patients with only impaired glucose tolerance.134,136 Finally, the plasma insulin response to abrupt elevation of plasma glucose levels normally shows a first sharp, spikelike phase.150 Before the plasma insulin level returns to baseline, it slowly rises again to produce a second plateau phase of more prolonged insulin release. The immediate first-phase response to glucose decreases in type 2 diabetes mellitus, as it does in the preclinical phase of type 1 diabetes mellitus, and is completely lost when the FPG level exceeds the normal range.151
Other Beta Cell Abnormalities
Another, previously neglected abnormality in type 2 diabetes mellitus is the presence of amyloid in close proximity to the islet beta cells. The amyloid fibrils have been found to contain amylin, a peptide that is cosecreted with insulin.152 Amylin deficiency parallels insulin deficiency in type 2 diabetes mellitus.152 Whether the accumulation of amyloid impairs beta cell function or is an epiphe-nomenon resulting from beta cell hyperfunction with increased amylin secretion in the early phases of the disease remains unclear.
More than 10% of some patient populations presenting with the clinical phenotype of type 2 diabetes mellitus have serum islet cell autoantibodies typical of type 1 diabetes mellitus, such as antibodies to GAD.153 This combination has been referred to as latent autoimmune diabetes in adults (LADA). These individuals exhibit a rapid decline in beta cell function, as shown by serum C-peptide levels, and they are likely to need insulin replacement therapy, even if their hyperglycemia is initially alleviated by oral beta cell stimulants.154,155
Metabolic Syndrome (Insulin-Resistance Syndrome)
The metabolic (insulin-resistance) syndrome is closely associated with, and often a forerunner of, type 2 diabetes mellitus. The metabolic syndrome has been defined both by the National Cholesterol Education Program and the World Health Organization (WHO) [see Table 6].156,157 Only the WHO definition includes insulin resistance per se, assessed by determining the ratio of the fasting plasma insulin level to the glucose level. By either definition, the syndrome represents a collection of risk factors not only for diabetes regulation but also for cardiovascular disease, and it presages both diseases. One obvious link between the components of the metabolic syndrome is obesity, which is a cause of insulin resistance158 and a contributor to the insulin resistance of type 2 diabetes melli-tus.159 Weight gain presages diabetes,160 and weight loss in obese individuals prevents progression of IGT to full-blown diabetes.161 Most patients with type 2 diabetes mellitus have abdominal obesity and many have dyslipidemia, hypertension, and other features of the metabolic syndrome.129 Abdominal obesity is itself a risk factor for type 2 diabetes mellitus and cardiovascular disease.162 The interrelationship of the metabolic syndrome, diabetes, and cardiovascular disease is exemplified in the NHANES III study. The overall prevalence of the metabolic syndrome in the United States is 23% in men and women older than 20 years and 44% in those older than 50 years.163 This huge prevalence of the metabolic syndrome reflects the burgeoning of obesity in the population. In the over-50 age group, 87% of those with diabetes, 71% of those with IFG, and 33% of those with IGT also had the metabolic syndrome.164 The prevalence of coronary heart disease (CHD) was 8.7% in those with neither diabetes nor the metabolic syndrome and 7.5% in those with only diabetes, but it increased to 13.9% in those with only the metabolic syndrome and to 19.2% in those with both the metabolic syndrome and diabetes. These cross-sectional data suggest that the metabolic syndrome is more potent than diabetes per se as a risk factor for CHD, but hyperglycemia (diabetes) aggravates the risk inherent in the metabolic syndrome. This relation explains much but not all of the vulnerability of patients with type 2 diabetes mellitus to cardiovascular complications resulting from accelerated atherosclerosis. On the other hand, not all patients with the metabolic syndrome and IGT go on to experience fullblown type 2 diabetes mellitus. A large randomized controlled trial is currently testing the ability of lifestyle changes (weight reduction and regular exercise) and the drug metformin to reduce the risk of progressing from IGT to type 2 diabetes mellitus.
Genetic Factors
Type 2 diabetes mellitus has a strong hereditary component. In virtually all monozygotic twinships, the disease develops in both individuals, often within a few years of each other.166 Offspring and siblings of diabetic patients are at great risk for the disease.
Table 7 American Diabetes Association Plasma Glucose Diagnostic Criteria for Diabetes Mellitus
|
Test Condition |
||
|
Plasma Glucose (mg/dl) |
||
|
Diagnosis |
Fasting > 8 hr |
2 hr after 75 g Oral Glucose |
|
Normal |
<110 |
<140 |
|
Impaired glucose tolerance (IGT) |
<126 |
>140-<200 |
|
Impaired fasting glucose (IFG) |
>110-< 126 |
< 200 |
|
Diabetes mellitus |
> 126 |
— |
|
Diabetes mellitus |
<126 |
> 200 |
|
Diabetes mellitus (Classic symptoms + casual plasma glucose, > 200 mg/dl) |
— |
— |
|
Gestational diabetes mellitus (GDM) |
Plasma Glucose (mg/dl) |
|
|
Fasting |
After 100 g Oral Glucose |
|
|
1 hr > 190* |
||
|
> 105* |
2 hr > 165* |
|
|
3 hr > 145* |
||
Note: The Fourth International Workshop-Conference on Gestational Diabetes Mellitus has proposed lower criteria, which would increase the percentage of cases from 4% to 7% in white women. These criteria are fasting, 95; 1 hour, 180; 2 hours, 155; and 3 hours, 140, after 100 g oral glucose.
*Two of these four criteria must be met for diagnosis of GDM.
No HLA markers have been identified for type 2 diabetes mellitus, in contrast to type 1 diabetes mellitus. Most current thinking is that the common forms of type 2 diabetes mellitus represent a complex multigenic disorder. Examination of the mechanism of action of insulin [see Figure 4] suggests many logical candidate genes, mutations of which could lead to type 2 diabetes mellitus by causing primary insulin resistance. Thus far, genes for insulin, the insulin receptor, insulin receptor substrate, glucose transporter, protein tyrosine phosphatase (which inactivates the insulin receptor), muscle hexokinase, glycogen synthase, and other insulin target enzymes have all been excluded as the cause of so-called garden-variety type 2 diabetes mellitus.167 Because of the association with obesity, genes that could cause obesity are also being investigated (e.g., leptin, uncoupling protein, and beta3-adrenergic receptor). The positional cloning approach being used in populations with high diabetes prevalence, such as Pima Indians and Mexican Americans, has yielded hints of loci on certain chromosomes that require confirmation.
There is one form of diabetes, MODY [see Table 1], that does have genetic specificity. In this disorder, mutations of several different genes on different chromosomes lead to a common phe-notype resembling type 2 diabetes mellitus, but the disorder begins at an early age.168 One of the genes codes for glucokinase, an enzyme that plays a key role in stimulation of insulin secretion by glucose.169 Another mutation occurs in a molecule known as insulin production factor-1, a transcription factor responsible for differentiation of precursor cells into beta cells capable of insulin secretion.168 Two other genes responsible for MODY code for hepatic transcription factor-1 and hepatic transcription factor-4, which, despite their names, operate in beta cells to regulate the glucose responsive pathway of insulin secretion.168 All of these genetic abnormalities more likely explain type 2 diabetes melli-tus caused by beta cell dysfunction than that caused by peripheral insulin resistance. Their functional relation to the diabetic diathesis is still obscure. Even in a phenotypically well defined monogenic form of diabetes such as MODY, the existence of many alleles for hepatic transcription factor-1 indicates the genetic complexity of diabetes. Although the mutations responsible for MODY account for only a minute fraction of all cases of type 2 diabetes mellitus, they encourage the view that genes contributing to most or all cases of type 2 diabetes mellitus will eventually be found.
Impaired glucose tolerance
The state known as IGT is associated with a future risk of development of diabetes of 1% to 10% a year, with different levels of risk for different ethnic groups. Equally important is the association of IGT with the metabolic syndrome [see Table 6], which includes hyperinsulinemia, glucose intolerance, dyslipidemia, hypertension, and impaired fibrinolysis. Presence of this syndrome constitutes a high risk for atherosclerosis, cardiovascular disease, thrombotic events, and mortality. The category of impaired fasting glucose was established by the American Diabetes Association as an intermediate zone between the upper limit of normal and the lower limit for dia-betes.1 IFG is also associated with increased risk of diabetes and cardiovascular disease. IFG and IGT are not identical states. About one third of people with IGT have IFG, one third of those with IFG have IGT, and one third of affected individuals have both.2 The pathophysiologic bases and clinical significance of the differences between IFG and IGT remain to be determined. Both conditions can be thought of as early stages of type 2 diabetes mellitus and can be referred to as prediabetes.
Prevention of type 2 diabetes
Five randomized clinical trials have recently demonstrated that the risk of progression from IGT to diabetes can be significantly reduced by lifestyle modifications or pharmacologic interventions. The Diabetes Prevention Program (DPP),170 the Finnish Diabetes Prevention Study,171 and the Da Qing IGT and Diabetes Study172 showed that intensive diet and exercise therapy brought reductions ranging from 42% to 58% in the progression from IGT to diabetes over 3 to 6 years. The weight loss achieved and the amount of exercise performed were modest—5.6 kg and 150 minutes of brisk walking a week in the DPP. The DPP also had a placebo-controlled metformin (850 mg twice daily) treatment arm, which showed a 31% reduction in diabetes. Most of this effect persisted after a 1-week washout from metformin. In the STOP-NIDDM trial, 100 mg of acarbose three times daily, compared with placebo, reduced diabetes development by 25%.173 Finally, in a group of Hispanic women with previous gestational diabetes, 400 mg of troglitazone daily, compared with placebo, reduced development of diabetes.174 This benefit was still present after an 8-month drug washout.
The efficacy, safety, and consistency of lifestyle interventions are impressive, but long-term follow-up is needed to determine how long such patients will continue to implement this therapy and how durable the benefits will be from either lifestyle changes or drugs. Equally important is whether cardiovascular disease events will be reduced eventually. A preliminary report from the first 3 years of the STOP-NIDDM trial suggests an encouraging significant reduction in myocardial infarction and total cardiovascular disease events.
