Possible mechanisms by which pancreatic cancer could contribute to the development of type 2 diabetes include the following: (1) destruction of islets, (2) impairment of the insulin secretory mechanism, (3) development of insulin resistance, and (4) tumor-related pancreatitis. Insulin and C-peptide measurements during oral glucose tolerance testing in patients with pancreatic cancer have shown abnormal β cell function with reduced plasma C-peptide responses in 50% of patients and increased plasma proinsulin-to-C-peptide ratios61,62 Insulin resistance has been demonstrated in most patients with pancreatic carcinoma.63–65 Morphometric studies of tumor-free regions of the pancreas have shown reduced β cell populations.66 An inverse correlation was noted between the number of β cells and the fasting plasma glucose concentration. These data can be interpreted as indicating that pancreatic cancers produce substances or responses that destroy normal β cells.64–67 The presence of diabetes in patients with pancreatic cancer predicts that the tumor is less likely to be respectable and the patient has a poorer prognosis than if diabetes is not present.53 Patients with pancreatic cancer typically have type 2 diabetes; most have been treated with oral antihyperglycemic agents.52,53
Several very intriguing observations that were reported recently make this relationship between pancreatic cancer and diabetes mellitus even more complex and confusing. Li et al. reported that metformin treatment of diabetic patients was associated with a decreased risk of developing pancreatic carcinoma, while insulin or insulin secretogogue treatment was associated with an increased risk.68 In a large, multicenter clinical trial that compared the treatment of type 2 diabetic patients with rosiglitazone-based therapy versus metformin plus sulfonylurea therapy, the development of pancreatic cancer during the study was statistically less frequent in the rosiglitazone arm than in the active comparator arm (2 cases versus 13 cases; P < .007).69
HEMOCHROMATOSIS
Hemochromatosis is an autosomal recessive genetic disorder that results in excessive deposition of iron in parenchymal cells of the liver, pancreas, muscle, heart, anterior pituitary, and other organs.70,71 The clinical diagnosis in the past was made by the findings of diabetes mellitus, hepatomegaly, and skin pigmentation. More recently, it has been recognized through biochemical and genetic testing.72 The first phenotypic expression of the disease is an elevation in serum transferrin saturation. This abnormality is followed by iron accumulation in the tissues and an elevation in the serum ferritin concentration. Early clinical findings are related to hepatic dysfunction and joint symptoms. Clinical diabetes mellitus and skin pigmentation occur relatively late in the course of the disease.71 A candidate gene for human leukocyte antigen (HLA)-linked hemochromatosis has been cloned and a mutation (C282Y) of the HFE gene identified that may account for 60% or more of cases of hereditary hemochromatosis. Another mutation (H63D) has been identified more recently.73
Diabetes mellitus has been reported in 50% to 60% of patients with hemochromatosis.71,74 Another 20% to 30% had glucose intolerance. These figures represent data from older series in which the diagnosis was made late in the course of the disease. Diabetes mellitus is more frequent in patients who have a family history of diabetes mellitus.
Follow-up of 237 patients who were given a diagnosis of hemochromatosis and treated at a single center from 1983 through 2005 has diabetes mellitus associated with the disease.73 Before 1996, hemochromatosis was diagnosed by the classic clinical and laboratory features of the disease. Since 1996, genetic testing, which is now available commercially, made it possible for them to diagnose hemochromatosis in asymptomatic patients. Of 45 patients diagnosed before 1996, 30.2% had cirrhosis of the liver and 35.6% had diabetes mellitus. After 1996, 192 patients were given the diagnosis of hemochromatosis (34% by family screening and 40% by clinical suspicion) and only 7.5% had cirrhosis of the liver and 17.7% had diabetes mellitus at the time of diagnosis. It is obvious that early through genetic testing and effective treatment can significantly reduce development of the complications of hemochromatosis. Of note was the observation that performing phlebotomy and reducing tissue iron in well-established clinical disease did not improve diabetes or lessen its management requirements. Thus early diagnosis and treatment is primarily preventative.73
Before 1996, hemochromatosis was diagnosed by the classic clinical and laboratory features of the disease. Since 1996, genetic testing, which is now available commercially, has made it possible to diagnose hemochromatosis in asymptomatic patients. Of the 45 patients diagnosed before 1996, 30.2% had cirrhosis of the liver and 35.6% had diabetes mellitus. After 1996, 192 patients were given the diagnosis of hemochromatosis (34% by family screening and 40% by clinical suspicion); only 7.5% had cirrhosis of the liver and 17.7% had diabetes at the time of diagnosis. It is obvious that early diagnosis through genetic testing and effective treatment have significantly reduced development of the complications. Of note is the observation that performing phlebotomy and reducing tissue iron did not improve diabetes or lessen its management requirements. Thus early diagnosis and treatment is primarily preventative.73
The metabolic studies that have been done show that patients with hemochromatosis have marked insulin resistance. Histologic study of the pancreas shows iron deposits that are greatest in the acinar cells but do involve islet cells. Insulin secretion in response to glucose or arginine is decreased; however, glucagon secretory responses to arginine are increased and unaffected by glucose.75,76 The data are compatible with a marked reduction in β cell function and no disturbance in α cell function. The hyperglycemia is a result of insulin resistance and decreased β cell function. The prevalence of diabetes mellitus probably could be reduced by early diagnosis of hemochromatosis and initiation of phlebotomy therapy.
Therapy for patients with hemochromatosis and clinical diabetes frequently requires insulin (40% to 50% of patients), although no systematic studies of therapy have been done.72 Reduction of tissue iron stores, although most beneficial in the early stages of disease, nonetheless can help improve glycemic control in 35% to 45% of patients.70,71
HEMOSIDEROSIS
Excessive iron deposition occurs in a variety of conditions other than primary hemochromatosis. In thalassemia major, frequent blood transfusions are necessary and may lead to massive iron overload. The reported prevalence of diabetes mellitus in treated thalassemia major is about 16%. This figure is highly correlated with the number of blood transfusions given and the duration of the disease. The incidence of IGT is reported to be 60%.77
Further evidence that deposits of excess tissue iron themselves are responsible for many of the metabolic abnormalities seen in hemochromatosis and thalassemia major comes from studies in rural male Bantus.78 Many Bantus drink alcoholic beverages that are brewed in iron containers and ingest in excess of 100 mg of iron per day. In those individuals, the prevalence of diabetes mellitus is 10-fold higher than in non–alcoholic beverage–consuming males.
Mechanistic studies in patients with thalassemia major with normal, impaired, and diabetic glucose tolerance tests show that increased iron stores are associated with the development of insulin resistance and a delay in early insulin secretion.79 A correlation between increased iron stores in normal women and the development of type 2 diabetes was demonstrated recently in the Nurses Health Study.80
CYSTIC FIBROSIS
Cystic fibrosis (CF) is a monogenetic disorder with abnormal cyclic adenosine monophosphate–regulated chloride channel activity. It is an autosomal recessive genetic disease with an incidence of 1 in 2500 live births in Caucasian populations. More than 1000 gene mutations have been identified in the CF gene.81 Organs as diverse as the lung, exocrine pancreas, large and small intestine, hepatobiliary system, and sweat glands are involved. Failure to secrete Na+, HCO3−, and water leads to retention of enzymes in the pancreas and ultimately to destruction of pancreatic tissue.82–84 Histologic examination of the pancreas in patients with CF shows fatty infiltration, necrosis, and fibrosis of the exocrine pancreas. Islet cell architecture is disrupted and the absolute number of pancreatic islets diminished. Islets that are present show significant decreases in β cells, α cells, and pancreatic polypeptide–producing cells and increases in δ (somatostatin-producing) cells. Islet amyloid deposits have been found in 69% of diabetic CF cases examined.
Diabetes mellitus requiring medical therapy (usually insulin) has been reported in 4.9% of patients of all ages with CF in a large European study of 1348 patients85 and in 5.1% of 18,627 patients of all ages monitored at CF centers in the United States and Canada.82 Diabetes occurs more often in individuals who are homozygous for the most common CF mutation, ΔF508.82,86,87 Diabetes also occurs with greater frequency with increasing age; it has been reported in 32% of Danish patients who were older than 25 years. Routine oral glucose tolerance testing suggests that of the total CF population aged 5 years or older, 35% have normal glucose tolerance, 37% have IGT, 17% have CF-related diabetes without fasting hyperglycemia, and 11% have CF-related diabetes with fasting hyperglycemia.
Several features of CF-related diabetes are noteworthy. Autoantibodies to pancreatic heat shock protein 60 have been found to precede the development of glucose intolerance (IGT and diabetes) and to decline subsequently with the onset of glucose intolerance.88 The development of diabetes in patients with CF is characterized initially by abnormal oral glucose tolerance and a delay in oral glucose–stimulated insulin secretion, followed later by a decrease in total insulin, glucagon, and pancreatic polypeptide secretion.89 First-phase insulin secretion after intravenous glucose is reduced markedly in patients with CF compared with matched controls. Patients with CF with IGT have normal plasma free fatty acid levels as compared with matched controls.90 Their plasma tumor necrosis factor-α levels are elevated, and they have insulin resistance as measured by the hyperinsulinemic euglycemic clamp.90 Decreased translocation of Glut-4 glucose transporters in muscle was observed during the peak insulin effect. Patients with CF have an increase in hepatic glucose production and are resistant to suppression of hepatic glucose production by insulin even in the nondiabetic state.91 Peripheral insulin sensitivity is increased in healthy nondiabetic individuals with CF, but insulin resistance occurs later as IGT and diabetes develop, and patients experience additional complications related to their CF.92 The development of diabetes worsens pulmonary function and other clinical manifestations of CF and may increase mortality by up to sixfold.93 Insulin treatment appears to reduce the extent of this deterioration. Hyperglycemia in patients with CF can be intermittent or permanent. Intermittent hyperglycemia occurs with glucocorticoid therapy, infection, or stress and must be treated with insulin until it resolves. Permanent hyperglycemia is always treated with insulin.82,84 It is likely that patients with CF progress from intermittent hyperglycemia to permanent hyperglycemia as pancreatic destruction continues to occur.
A small short-term study (12 weeks) suggests that treatment of CF-related diabetes with glargine insulin may provide some advantages over treatment with NPH insulin.94
Microvascular complications have been observed in patients with CF-related diabetes with fasting hyperglycemia for longer than 10 years. Fourteen percent had microalbuminuria and 16% had retinopathy.95 Macrovascular disease appears to be uncommon.
Hyperglycemia Associated With Endocrinopathies
In the complex regulation of fuel homeostasis, many hormones other than insulin play a complementary role. Growth hormone (GH) by itself and through its synthesis of insulin-like growth factor-1 (IGF-1) controls many aspects of amino acid transport, protein synthesis, and lipid metabolism. Glucagon and catecholamines are counterregulatory hormones that protect against hypoglycemia and provide extra glucose when needed during stress states. Glucocorticoids exert both a permissive role in the normal physiologic regulation of gluconeogenesis and a pharmacologic role in providing increased glucose availability during stress. Somatostatin is a paracrine hormone that appears to act locally to help regulate the normal secretory patterns of GH, insulin, glucagon, and several gastrointestinal hormones.
The mechanisms responsible for the action of these various hormones are described in detail in other chapters. This section will address the unique characteristics of hyperglycemia as it relates to each endocrinopathy and its treatment.
ACROMEGALY
Acromegaly is characterized by excessive and autonomous secretion of growth hormone and IGF-1.96,97 The prevalence of overt diabetes mellitus reported in different series of acromegalic patients ranges from 30% to 56%.96,98 IGT may be present in as many as 36% of acromegalic patients.96 In a specific population, the percentage of acromegalic patients in whom diabetes mellitus will develop depends on the prevalence of predisposition to type 2 diabetes in the population and the magnitude of elevation of serum IGF-1 levels.
Elevated GH and IGF-1 levels cause excessive hepatic glucose production and impaired insulin-mediated muscle glucose uptake.99–101 This insulin resistance is correlated with circulating IGF-1 levels and has been demonstrated by the euglycemic hyperinsulinemic clamp and the minimal model techniques.
Reduction in circulating GH and IGF-1 levels by successful surgical removal of the tumor producing growth hormone or GH-releasing factor results in significant improvement in glycemic control in acromegalic patients with diabetes mellitus.100,102 Recent data suggest that circulating GH must be lowered to 2 ng/L and IGF-1 lowered to the normal range to be considered curative.97,103,104 Transsphenoidal surgery achieves growth hormone levels less than 5 ng/L in approximately 60% of patients. Curative levels are attained in about 70% of patients with microadenomas (<10 mm in diameter) but are attained considerably less often in those with macroadenomas of the pituitary.97,103
Use of the somatostatin analogue octreotide to treat acromegaly as the primary medical therapy or to supplement prior inadequate surgical treatment or radiotherapy has allowed attainment of greater and more consistent reductions in circulating GH and IGF-1 levels (GH levels ≤5 ng/L in 65% and ≤2 ng/L in 40%, and IGF-1 levels in the normal range in 64% of patients).103–105
Treatment of acromegalic patients with octreotide presents several issues with respect to glucose metabolism.103–106 Reductions in circulating GH and IGF-1 levels will decrease insulin resistance and should lead to improvement in glycemic control in subjects with diabetes mellitus or IGT. However, pharmacologic doses of a somatostatin analogue also reduce insulin secretion (decreased insulinogenic index), and such a reduction should cause a deterioration in glucose tolerance. Thus in any particular patient, octreotide therapy will modify glucose metabolism in accordance with these competing effects. Approximately two thirds of acromegalic patients with diabetes mellitus are treated with insulin and one third with oral hypoglycemic agents. Octreotide treatment in patients with diabetes mellitus and acromegaly frequently leads to improvement in glycemic control as measured by a reduction in the insulin dose, conversion from insulin therapy to oral hypoglycemic agent therapy, or conversion from oral hypoglycemic agent therapy to dietary management.103,106 Some patients (those with more severe insulin deficiency), however, will have significant deterioration in glycemic control.104,106 When higher doses of octreotide are given, IGT and even frank diabetes mellitus (as high as 20% and 29%, respectively) may develop in acromegalic patients with normal glucose tolerance before octreotide treatment.106 An alternative to treatment with somatostatin analogues is treatment with the GH receptor blocker Pegvisomant. This agent will decrease IGF-1 levels and can improve glycemic control.107,108 However, it does cause an increase in visceral fat and occasionally is associated with increased liver enzymes.109
Appropriate treatment for acromegaly is necessary to reduce the increased mortality that has been seen in the past.110 This increased mortality is due to cardiovascular, cerebrovascular, and neoplastic diseases. The best determinants of outcome in acromegalic patients are age at diagnosis, interval between symptoms and diagnosis, and mean long-term circulating GH and IGF-1 levels. Because insulin resistance and diabetes mellitus contribute significantly to cardiovascular risk, aggressive diagnosis and management of the diabetes mellitus associated with acromegaly are essential.
GROWTH HORMONE TREATMENT
The availability of recombinant DNA technology to make human GH has provided an opportunity to treat many GH-deficient individuals using this hormone. One consideration in treatment with recombinant human GH is the question of whether long-term treatment can lead to the development of diabetes mellitus.111 A recent study of glucose metabolism in 23,333 children and adolescents treated with human GH found a sixfold greater frequency of type 2 diabetes mellitus than predicted (34.4 cases per 100,000 years of GH treatment).112 In contrast, the frequency of type 1 diabetes was the same as expected. The data suggest that GH treatment accelerates the development of type 2 diabetes in individuals who have a genetic predisposition.
CUSHING’S SYNDROME
Glucocorticoids are insulin antagonistic hormones.113 When administered in pharmacologic doses, they increase basal hepatic glucose production and decrease the insulin-mediated effects caused by suppressing hepatic glucose production and increasing muscle glucose uptake.114–117 Insulin secretion is increased as a consequence of hepatic and peripheral insulin resistance.
Pharmacologic concentrations of glucocorticoids occur in disease states associated with autonomous secretion of adrenal cortical hormones (Cushing’s syndrome) or as the result of administration of such agents for the treatment of nonendocrine diseases. When sustained pharmacologic concentrations of glucocorticoids occur in normal individuals, increased insulin secretion maintains fasting plasma glucose within the normal range, but the postprandial plasma glucose concentration is elevated above normal in 25% to 90% of such individuals, depending on the magnitude of plasma glucocorticoid elevation.118 Individuals with limited β cell insulin secretory reserve are more subject to fasting hyperglycemia and type 2 diabetes mellitus. Ten percent to 20% of patients with Cushing’s syndrome have overt type 2 diabetes mellitus.119–123 Among renal transplant recipients receiving long-term corticosteroid therapy, steroid-induced diabetes mellitus has been reported to develop in as few as 5.5% and as many as 46% of patients.124,125 Factors that influence the development of diabetes mellitus during corticosteroid therapy include a family history of diabetes mellitus, increasing age, obesity, and both average daily and total cumulative corticosteroid dose.126,127 In individuals with a previous onset of diabetes mellitus, administration of glucocorticoids significantly worsens glycemic control and requires modification of diabetes management.
Recent studies have documented that steroid-induced diabetes mellitus occurs in adrenal disorders other than those associated with frank Cushing’s syndrome. Measurement of oral glucose tolerance in 64 consecutive patients with “nonfunctioning” adrenal adenomas identified normal glucose tolerance in 25, glucose intolerance in 17, and diabetes mellitus in 22, including 6 patients with previously diagnosed diabetes mellitus.128 Autonomous cortisol secretion without the clinical stigmata of Cushing’s syndrome has been recognized recently as preclinical Cushing’s syndrome. A retrospective study of 63 such individuals found that 17.5% had diabetes mellitus.129 A cross-sectional study of 90 obese, poorly controlled type 2 diabetic patients found that 3 had the preclinical Cushing’s syndrome abnormality.110 Excess IGT and diabetes mellitus have been reported in hypopituitary adults receiving conventional replacement therapy and may be related to the intermittently higher plasma levels that occur after dosing than would occur under normal hypothalamic-pituitary-adrenal axis function.130
Some insight into the mechanisms by which glucocorticoids cause diabetes mellitus was obtained by investigating the effects of administration of dexamethasone on oral glucose tolerance, on glucose turnover under basal conditions and during glucose infusion, and on the insulin response during hyperglycemic clamp studies in normal individuals who had been characterized previously as low insulin responders or high insulin responders.131 Dexamethasone caused a higher fasting plasma glucose concentration, a greater rise in plasma glucose, and a lesser rise in plasma insulin during the oral glucose tolerance test in the low insulin responders than in the higher insulin responders. A diabetic oral glucose tolerance test result was obtained in three of the six low and none of the six high insulin responders. Dexamethasone increased hepatic glucose production only in the low insulin responders and increased insulin secretion during the hyperglycemic clamp study only in the high insulin responders. The conclusion drawn from these studies is that type 2 diabetes develops when plasma glucocorticoids are elevated in individuals with limited β cell secretory function.
Steroid-induced diabetes may be permanent or transient. In general, insulin is required for treatment if the fasting plasma glucose concentration exceeds 180 mg/dL.132 At lesser levels of fasting hyperglycemia, many physicians treat the hyperglycemia with oral antihyperglycemic agents. Very few studies have evaluated the efficacy of pharmacologic treatment of steroid-induced diabetes mellitus. Because insulin resistance is a major abnormality, perhaps the combination of insulin sensitizers and insulin would be most effective. A reduction in corticosteroid dose or secretion improves glycemic control and in some individuals may even reverse the diabetes. The more severely elevated the fasting plasma glucose concentration, the less likely it is that reducing corticosteroid levels will reverse the diabetes. Ketoacidosis is very uncommon with steroid-induced diabetes or Cushing’s syndrome. Hyperosmolar nonketotic coma, however, is not uncommon.133
GLUCAGONOMA SYNDROME
Glucagon plays a primary role in facilitating the uptake of amino acids by the liver and their conversion into glucose by gluconeogenesis. Excess and unregulated glucagon secretion alone or in conjunction with other islet hormones occurs in some islet cell tumors. A classic syndrome has been described in individuals who have tumors secreting high quantities of glucagon. This syndrome was initially recognized in 1974 and is referred to as the glucagonoma syndrome.134 Features of this syndrome include necrolytic migratory erythema, mild non–insulin-requiring type 2 diabetes mellitus, glossitis, angular cheilitis, weight loss, and anemia.135,136 Laboratory studies show markedly elevated plasma glucagon levels and severe hypoaminoacidemia (<25% normal).
Glucagonomas are rare, with a reported incidence of 1 case per 20 to 200 million population. Several reviews of the literature indicate that most tumors occur in the tail of the pancreas (reported in 54% to 68%); they have an average tumor diameter of 3.6 cm (but as many as one third are less than 2 cm), are malignant in about two thirds of cases, and have metastases in other organs in 51% to 54% of patients at the time of diagnosis.137,138 The diabetes mellitus is characterized by mild hyperglycemia and is nonketotic. The tumors are relatively slow growing, and the 10-year survival rate is 52% in those with metastases and 64% in those without metastases.
The hyperglycemia is due to excess glucose production by the liver. The hypoaminoacidemia results from an increase in amino acid clearance.139 Necrolytic migratory erythema, glossitis, weight loss, and anemia are in large part a consequence of the protein malnutrition.136 Deep venous thrombosis that is not associated with coagulation disorders is common.
All components of the syndrome are improved if the hyperglucagonemia can be reduced. Treatment consists of surgical removal of the tumor, followed by hepatic artery embolization if necessary for liver metastases.136,140 Octreotide treatment has been very effective in reducing residual plasma glucagon levels.136,140 Cytotoxic agents such as streptozotocin and fluorouracil may be valuable as additional modes of therapy. Zinc and amino acid supplementation has been used to treat the rash but is relatively ineffective if plasma glucagon levels remain very high. Antiplatelet therapy should be used to prevent venous thrombosis. The hyperglycemia, although mild, generally requires treatment with an antihyperglycemic agent. Insulin would appear to be the most appropriate agent, although few or no clinical outcome data are available to support this hypothesis. Treatment of the hyperglucagonemia will ameliorate the hyperglycemia in most cases.140
SOMATOSTATINOMA
Case reports of patients with hyperglycemia and a pancreatic tumor containing large quantities of somatostatin first appeared in 1977.141,142 One of those patients became euglycemic after complete resection of the tumor was performed. Since that time, it has been recognized that large somatostatin-producing pancreatic tumors may be associated with a clinical syndrome consisting of hyperglycemia, cholelithiasis, steatorrhea, and hypochlorhydria.143
Somatostatin-producing tumors arising from the gastrointestinal tract and the pancreatic islets have been reported.144 Duodenal somatostatinomas with and without von Recklinghausen’s disease are seldom associated with recognizable somatostatinoma syndrome, often contain psammoma bodies, and may be associated with demonstrable metastases at the time of surgery.144 The clinical features of pancreatic somatostatin-producing tumors are variable, and this variation is related to differences in the quantity and qualitative features of somatostatin variants that are synthesized and secreted by these tumors.145–147 Marked differences in the degree to which insulin, glucagon, and growth hormone secretion are affected in various patients with pancreatic somatostatin-producing tumors probably account for some of the variation in the clinical syndrome. Hyperglycemia in patients with pancreatic somatostatinomas can vary from mild to modest hyperglycemia to severe diabetic ketoacidosis.144,148,149
Somatostatin infusions in humans are associated with a pronounced decrease in bile flow and bile acid secretion and an increase in bile cholesterol saturation.150 In vitro, somatostatin has a direct inhibitory effect on cholecystokinin stimulation of gallbladder contraction.151 These observations provide a basis for understanding the cholelithiasis and steatorrhea commonly seen with pancreatic somatostatinomas. Additionally, they explain the development of gallstones in 23.5% of acromegalic patients treated with octreotide during the first year of treatment.103
The hyperglycemia seen as part of the somatostatinoma syndrome most likely is related to suppression of insulin secretion. In some patients, a relative insulin deficiency leads to reduced peripheral glucose utilization without impairing suppression of hepatic glucose production.152 In more severe suppression of insulin secretion, both features of insulin action are reduced.
Somatostatin-producing tumors are rare, usually asymptomatic, or only mildly symptomatic and frequently remain undiagnosed for many years. The diagnosis frequently is made late and the prognosis is poor because of extensive metastases. The use of somatostatin receptor scintigraphy with indium 111–labeled pentetreotide promises to improve the ability to detect somatostatinomas earlier.153 Early diagnosis and surgical removal can lead to cure, but medical treatment has produced questionable results. A recent study suggests that somatostatinomas possess functioning somatostatin receptors and that octreotide therapy (0.5 mg/day subcutaneously) can effectively decrease somatostatin production by the tumor and improve diabetes and diarrhea.153
PHEOCHROMOCYTOMA
Glucose intolerance occurs in about 30% of patients with pheochromocytoma, but overt diabetes mellitus is uncommon.154 Mechanisms responsible for glucose intolerance include suppression of insulin by α-adrenergic receptor stimulation of β cells; an increase in insulin resistance, probably related to elevated plasma free fatty acid levels; and increased hepatic glucose output as a result of β-adrenergic stimulation of hepatocytes. α-Adrenergic receptor blockade improves glucose tolerance and insulin secretion.155,156 Removal of the pheochromocytoma restores glucose tolerance to normal in most cases. Treatment of glucose intolerance with antihyperglycemic agents is rarely required.153
Drugs That Can Cause Hyperglycemia
Blood glucose is regulated by the balance between insulin secretion and insulin action. A drug that destroys β cells or blocks their insulin secretory function will cause hyperglycemia in any individual (Table 43-5). A drug that directly or indirectly increases insulin resistance can cause hyperglycemia only in individuals with β cells that have limited insulin secretory reserve (individuals with a predisposition to type 2 diabetes). Several recent reviews on drug-induced disorders of glucose metabolism are available.157–159
Table 43-5. Drugs That Interfere With Insulin Secretion
Decrease Ca2+ entry
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