Keywords

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

1 Introduction

The diabetic syndromes include type 1 diabetes with immune destruction of the pancreatic islets, type 2 diabetes with a complex pathophysiology of insulin resistance combined with insulin secretory failure, distinct monogenetic abnormalities (maturity onset diabetes of the young – MODY), and extreme insulin resistance of several different etiologies. In addition, secondary causes of diabetes mellitus refer to a category in which diabetes is associated with other diseases or conditions. Presumably, the diabetes is caused by those conditions and could be reversed if those conditions were cured.

Secondary causes constitute less than 2% of total cases of diabetes mellitus. Mechanistically they can be considered in the broad categories of decreased insulin secretion, insulin resistance, and increased counter-regulation, although classification schemes are typically anatomical and pathophysiological (Table 16.1).

Table 16.1 Classification of secondary causes of diabetes mellitus
Full size table

Decreased insulin secretion is generally seen in pancreatic diabetes following destruction of the endocrine pancreas with loss or impairment of insulin secretion and in somatostatinoma. Liver disease causes insulin resistance via unknown mechanisms. Counter-regulatory hormones balance the glucose-lowering action of insulin. Excess levels of the counter-regulatory hormones glucagon, catecholamines, cortisol, and growth hormone seen with exogenous administration or excess secretion by their respective tumors can elevate the blood glucose level. The pathogenesis of secondary diabetes is sometimes defined to include autoimmune mechanisms and antagonism of insulin action (discussed in other chapters). There are also a variety of infections (congenital rubella, cytomegalovirus) and rare genetic syndromes that are associated with insulin resistance or diabetes mellitus through unknown mechanisms.1

2 Diseases of the Exocrine Pancreas

2.1 Acute Pancreatitis

Acute inflammation of the pancreas can cause transient glucose elevation.2 The incidence of abnormal carbohydrate metabolism in acute pancreatitis varies from 8 to 83%.3 The wide range can be related to the cause of acute inflammation, with alcohol having a more damaging effect on pancreatic tissue and a higher incidence of glucose intolerance.4 Hyperglycemia has also been correlated with tissue necrosis and a higher mortality.2 , 5 The plasma insulin concentration is lower in patients with acute pancreatitis than in healthy control subjects and is associated with impaired insulin secretion in response to glucose or glucagon. Glucagon concentration is usually elevated and tends to remain high for at least 1 week.6 , 7 Hyperglycemia usually subsides within weeks of the acute attack. However, 24–35% of patients have glucose intolerance and 12% have diabetes mellitus following a single bout of acute pancreatitis.8

2.2 Chronic Pancreatitis

Chronic pancreatitis is an inflammatory condition that influences both digestive and endocrine function of the pancreas.9 Although glucose intolerance is frequent in patients with chronic pancreatitis, overt diabetes mellitus usually occurs late in the course of the disease. Patients with chronic calcifying pancreatitis are at higher risk (60–70%) of developing diabetes and glucose intolerance than are patients with non-calcifying disease (15–30%),10 with both insulin and glucagon secretion disturbed more strongly in calcific than in noncalcific pancreatitis.11 Diabetes caused by chronic pancreatitis requires insulin therapy because of β-cell destruction, although lack of immunologic destruction may contribute to a slower destruction of the β-cells in chronic pancreatitis than in type 1 diabetes with greater preservation of β-cell function. Concomitant damage to the glucagon-secreting alpha cells results in a high incidence of hypoglycemia, with residual counter-regulation attributable to catecholamine secretion.12 Despite the requirement for insulin in diabetes mellitus secondary to chronic pancreatitis, glucagon-like peptide 1(7–36) amide (GLP-1), an intestinally derived insulinotropic hormone, may be considered in select patients with preservation of α- and β-cell secretory capacity.13 Neuropathy and retinopathy occur in increased frequency in these patients, while nephropathy and diabetic ketoacidosis are rare.14

2.3 Pancreatic Cancer

Impaired glucose tolerance, an early manifestation of pancreatic cancer in over 40%, may occur before the tumor becomes apparent.15 Pancreatic cancer may be associated with abnormal islet cell function by primary alteration of islet cells by carcinogen, secondary damage by cancer cells,16 or stimulation of the secretion of islet amyloid polypeptide (IAPP) through an unknown mechanism. IAPP causes cytotoxicity and apoptosis.17 , 18 It was found that pancreatectomy in pancreatic cancer with diabetes mellitus and high level of IAPP is associated with the cure of diabetes and the disappearance of IAPP.19

2.4 Pancreatectomy

Total pancreatectomy, primarily used for the treatment of pancreatic cancer with large lesions in the head of the pancreas, is associated with a high incidence of glucose intolerance. Pancreatic resections that spare the duodenum, such as distal pancreatectomy, are associated with a lower incidence of new or worsened diabetes than is the standard or pylorus-preserving pancreaticoduodenectomy (Whipple procedure) or total pancreatectomy.

In addition to insulin deficiency, the endocrine abnormalities that accompany pancreatic resection can include pancreatic polypeptide (PP) deficiency with preservation of glucagon production if the resection is proximal or glucagon deficiency if the resection is distal. Glucagon deficiency increases susceptibility to hypoglycemia through loss of counter-regulation, and PP deficiency is considered to impair hepatic insulin action, thereby contributing to hyperglycemia. The resulting hepatic insulin resistance with persistent endogenous glucose production and enhanced peripheral insulin sensitivity results in a brittle form of diabetes, which can be difficult to manage.20

2.5 Cystic Fibrosis-Related Diabetes (CFRD)

Cystic fibrosis (CF) comprises a clinical triad of abnormalities involving the sweat glands, the exocrine pancreas, and the respiratory epithelium. CFRD, the principal extra-pulmonary complication of cystic fibrosis, occurs in 15–30% of adults with mean age of onset of 18–21 years21 , 22 and up to 1% of children with the disease.23 CFRD is primarily an insulinopenic condition. Early in the course of the disease, the β-cells appear normal. As the disease progresses, insulin secretion is impaired and delayed as a result of β-cell failure secondary to fibrosis, fatty infiltration, and amyloid deposition. Insulin resistance plays only a minor role. CFRD is associated with worsening of nutritional status, increased morbidity, decreased survival, and decrease in pulmonary function in patients with CF.24 Early treatment with insulin may decrease morbidity.25

2.6 Pancreatic Infiltrative Diseases

2.6.1 Primary/Secondary Hemochromatosis

Hemochromatosis (bronze diabetes) is a state of iron overload due to either hereditary or secondary (acquired) causes. The acquired causes include transfusional iron overload anemias (thalassemia major, sideroblastic anemia, and chronic hemolytic anemia), chronic liver diseases (hepatitis C, alcoholic liver disease, nonalcoholic fatty liver),26 and dietary or parenteral iron overload. Deposition of iron in the pancreas causes fibrosis and secondary diabetes in 30–60% of patients with advanced disease. Contributing factors include an inherited predisposition for diabetes mellitus, cirrhosis, and direct damage to the pancreas by deposition of iron.27

Although the exact mechanism of iron-induced diabetes is uncertain, iron excess seems to contribute initially to insulin resistance and subsequently to decreased insulin secretion as well as hepatic dysfunction.28 Pancreatic islets have an extreme susceptibility to oxidative damage from iron-derived free radicals, perhaps because of the reliance on mitochondrial metabolism of glucose for glucose-induced insulin secretion, and low expression of the antioxidant defense system (Table 16.2).29

Table 16.2 Frequency of diabetes mellitus in pancreatic diseases
Full size table

3 Abnormalities of the Endocrine Pancreas and the Endocrine Gut

β-Cells of the pancreas are responsible for insulin secretion and glucose homeostasis. Abnormalities in the non-β-cells of the pancreas can also be associated with abnormalities in glucose metabolism and cause glucose intolerance or secondary diabetes. Endocrine tumors of the non-β-cells of the pancreas and/or the gut that cause glucose intolerance include the following:

  1. 1.

    Hypersecretion of glucagon (glucagonoma)

  2. 2.

    Hypersecretion of somatostatin (somatostatinoma)

  3. 3.

    VIPoma (vasoactive intestinal peptide tumor)

  4. 4.

    Hypersecretion of gastrin (gastrinoma)

  5. 5.

    Carcinoid syndrome

3.1 Glucagonoma

The glucagonoma syndrome is a rare disorder of a glucagon-secreting tumor, with an annual incidence of 0.1 cases per million.30 , 31 Presentation is usually in the fifth decade of life, with an even distribution between females and males. The tumors arise almost exclusively in the pancreas and are malignant in behavior, with 50% having metastasized to liver or lymph nodes at the time of diagnosis. Patients develop the “4D syndrome” of diabetes, dermatitis (necrolytic migratory erythema), deep-vein thrombosis, and depression. Hypersecretion of glucagon also produces glucose intolerance in 80% of patients, with or without frank diabetes mellitus.32 Glucagon is one of the “counter-regulatory” hormones that balance the glucose-lowering action of insulin with actions to raise the circulating glucose levels. Glucagon increases hepatic glucose output via glycogenolysis and gluconeogenesis33 causing hyperglycemia in the glucagonoma syndrome.

3.2 Somatostatinoma

Somatostatinomas are neuroendocrine tumors that usually originate in the pancreas or the intestine. The release of large amounts of somatostatin causes a distinct clinical syndrome characterized by diabetes mellitus, gallbladder disease, diarrhea, and weight loss. The development of diabetes mellitus is likely secondary to the inhibitory action of somatostatin on insulin release as well as replacement of functional pancreatic tissue.34 , 35

3.3 VIPoma Syndrome

The VIPoma syndrome is due to a rare pancreatic endocrine tumor that secretes excessive amounts of vasoactive intestinal peptide (VIP). This causes a distinct syndrome of fasting large volume diarrhea, hypokalemia, and hypochlorhydria (due to gastric acid suppression). Hyperglycemia is noted in 25–50% of patients with VIPomas. It has been attributed to the glycogenolytic effects of VIP on the liver.36

3.4 Gastrinoma (Zollinger–Ellison) Syndrome

Zollinger–Ellison (ZE) syndrome is characterized by gastrin-producing tumors (gastrinoma), hypersecretion of gastric acid, and recurrent peptic ulcers. The tumors usually originate from the pancreas and less frequently from the duodenum. Glucose intolerance and diabetes have been reported in patients with ZE syndrome.37 It is unclear if gastrin overproduction is the cause of glucose intolerance. Twenty to sixty percent of patients with ZE syndrome have gastrinoma as part of the genetic multiple endocrine neoplasia (MEN) syndrome.

3.5 Carcinoid Syndrome

One report focuses on the link between diabetes mellitus and carcinoid tumors, relating a 50–80% incidence of diabetes or glucose intolerance to active secretion of serotonin.38 It is more probable that diabetes seen with carcinoid syndrome is related to tumor secretory products such as somatostatin, glucagon, or ACTH causing Cushing’s syndrome.39

4 Liver Disease as a Cause of Secondary Diabetes Mellitus

The liver plays a major role in glucose homeostasis.40 It produces glucose by both glycogenolysis (breakdown of glycogen) and gluconeogenesis (newly synthesized glucose). It is a major organ in glucose storage in the form of glycogen.

Insulin increases hepatic glucose uptake and suppresses hepatic glucose production. This results in increase in glycogen synthesis and deposition in the liver. Opposing this action, glucagon decreases hepatic glucose uptake from the portal system.

4.1 Nonalcoholic Fatty Liver Disease (NAFLD), Chronic Hepatitis, and Cirrhosis

The incidence of impaired glucose tolerance and diabetes is increased in chronic liver disease.41 , 42 Insulin resistance is a characteristic feature of patients with liver cirrhosis.43 Even in the absence of cirrhosis, portal hypertension is associated with insulin resistance,44 manifested as insulin resistance in 80% of cirrhotic patients, with 20–60% developing overt diabetes mellitus.45 In total, an astounding 95% of patients with cirrhosis have diabetes or glucose intolerance.46 Both insulin resistance and inadequate insulin secretion by the β-cells contribute to glucose intolerance in patients with cirrhosis.43 Inflammatory pathways are invoked as a link between liver disease and glucose intolerance, especially in NAFLD.47 , 48 Hyperglycemia in chronic liver disease may also occur as a result of the therapeutic administration of various medications including interferons and corticosteroids. Cirrhotic patients with overt diabetes have a high mortality rate, with an increased risk of liver cell failure. Thus, the presence of diabetes in cirrhotic patients is a risk factor for long-term survival.46 , 49 , 50

4.2 Hepatitis C

Overt diabetes mellitus is more prevalent in patients with chronic hepatitis C than in patients with other liver diseases.51 – 57 Risk factors for the development of glucose intolerance in patients with hepatitis C include hepatitis C viremia, male gender, hypertension, BMI, and age.58 The mechanism by which hepatitis C virus (HCV) infection induces glucose intolerance and diabetes is unknown. Many theories, including cytopathic and immunological mechanisms, have been proposed for the effect of HCV on extrahepatic tissues.59 , 60 One possible mechanism is the upregulation of TNF-α by HCV. TNF-α has been shown to block tyrosine phosphorylation of insulin receptor substrate (IRS)-1, disrupting an important step in the insulin signaling cascade, with restoration of insulin sensitivity following administration of antibodies against TNF-α.61 The HCV core protein upregulates the suppressor of cytokine signaling (SOCS)3 and downregulates, via ubiquitination, insulin receptor substrates (IRS) 1 and 2.61 – 64 Thus, via these two mechanisms, the HCV core protein is thought to lead to insulin resistance. Insulin resistance impairs sustained response to antiviral therapy and is associated with increased severity of fibrosis in patients with chronic HCV.65 – 68

4.3 Acute Hepatitis

Acute hepatitis is associated with transient glucose intolerance or hypoglycemia,69 , 70 with rare persistence of diabetes.71 , 72

For more detailed discussion of the relationship between liver disease and diabetes, please see Chapter 35.

5 Drug-Induced or Chemical-Induced Diabetes

Many drugs are known to cause glucose intolerance or diabetes mellitus (Table 16.3).73

Table 16.3 Some drugs causing impaired glucose tolerance and diabetes
Full size table

Alcohol, when ingested acutely, has been associated with hypoglycemia due to its inhibitory effect on gluconeogenesis. This effect is mostly seen in fasted individuals with depleted glycogen stores who are dependent on gluconeogenesis to maintain hepatic glucose production. Acute large alcohol intake can cause insulin resistance in peripheral tissues, particularly in the muscles. When ingested on chronic basis, excessive alcohol intake has been associated with moderate to severe insulin resistance and glucose intolerance.

β-Adrenergic blockers are widely used in clinical practice. They are considered, along with diuretics, the first line of therapy for hypertension. They are known to promote hypoglycemia both by inhibiting hepatic glucose production directly and by blocking the counter-regulatory hormonal response to hypoglycemia. Studies have shown that non-diabetic patients on β-blockers (particularly the non-selective) may exhibit disturbance in their glucose homeostasis in the form of worsening glucose tolerance. This might be due to worsening insulin secretion or insulin action.

Pentamidine has multiphasic effect on the β-cell of the pancreas. Initially, pentamidine causes β-cell degranulation with the release of insulin, which results in hypoglycemia. Later, it causes β-cell destruction and impaired insulin secretion, resulting in hyperglycemia and even diabetic ketoacidosis.74 Intravenous pentamidine can permanently destroy pancreatic β-cells and has been incriminated in the development of secondary diabetes in multiple cases.75 , 76 These reactions, however, are considered rare. Impairment of insulin action can result from the administration of multiple drugs and hormones, such as nicotinic acid and steroids.77 , 78

Patients on α-interferon treatment for chronic hepatitis C are reported to develop diabetes with islet cell antibodies and, in some cases, insulin deficiency.79 Vacor (pyriminil, synthetic organic rodenticide) can cause hyperglycemia, ketoacidosis, and irreversible diabetes, in addition to its toxic effect on the central and peripheral nervous system.80

5.1 Protease Inhibitors, Human Immunodeficiency Virus (HIV), and Glucose Intolerance

Undesirable physical and metabolic changes associated with HIV infection and therapy assume greater importance as life expectancy improves.81 An acquired lipodystrophy syndrome occurs in a high proportion of chronically HIV-infected individuals and variably includes central obesity, dorsal fat pad, facial wasting, and wasting of the extremities. Insulin resistance, frank diabetes, and hyperlipidemia are associated with this lipodystrophy and presumably carry an increased risk of premature cardiovascular mortality.82 The metabolic syndrome can occur in HIV-infected individuals in the absence of HIV-specific medications, increases in incidence with the use of some classes of drugs including reverse transcriptase inhibitors, and is greatest in those patients on protease inhibitors.83 Investigation into mechanisms has included the role of mitochondrial toxicity in producing the syndrome, protection of lipid particles from degradation,84 increased fatty acid and cholesterol biosynthesis,85 inhibition of fat cell differentiation,86 and inhibition of glucose transport into fat and muscle.87 There is no accepted or proven safe therapy.

For detailed discussion of the relationship between HIV infection and diabetes, see Chapter 38.

6 Endocrinopathies

6.1 Acromegaly, a State of Growth Hormone Excess, Is Associated with Hyperglycemia and Insulin Resistance

The major players in the growth hormone (GH) system are GH and IGF-1 (insulin-like growth factor-1). GH and IGF-1 affect glucose and fat metabolism, as well as growth. They have opposing effects on carbohydrate metabolism (Fig. 16.1). A family of IGF-binding proteins (IGF-BPs) affects tissue delivery, availability of IGF-1, and gene transcription, thereby altering the balance between growth hormone and IGF-1. In some tissues, the IGF effects cooperate with the GH effects (for example, growth of long bones) and in other tissues, they are antagonistic (the metabolic effects).

Fig. 16.1
figure 16_1_105153_2_En

Growth hormone (GH) and IGF-1 have opposite effects on glucose metabolism. Hepatic IGF-1 appears to be an insulin sensitizer and can lower blood glucose levels, while elevated GH raises blood glucose and is associated with insulin resistance93

Full size image

Growth, mediated by IGF-1, is an anabolic process that requires cellular uptake of building components, such as amino acids and glucose. Administered separately from growth hormone, IGF-1 lowers elevated blood glucose levels and can cause hypoglycemia. In fact, IGF-1 has been used to treat diabetic ketoacidosis in insulin-resistant individuals.88

Growth hormone can be regarded as the metabolic partner of IGF-1 because growth hormone provides substrate for the effects of IGF-1. GH-stimulated fat mobilization and new glucose formation (gluconeogenesis) are required to make building components (substrate) available. Growth hormone acts on the fat cell to stimulate the hormone-sensitive lipase, causing lipolysis (breakdown of fat) with the release of glycerol and free fatty acids (FFAs). Glycerol is a precursor of hepatic gluconeogenesis. FFAs stimulate gluconeogenesis and are the precursors of ketogenesis.89 FFA elevation also increases output of the lipoprotein VLDL, thereby elevating triglyceride levels.90 FFAs become the preferred substrate for muscle uptake and oxidation. GH also causes inhibition of muscle uptake and oxidation of glucose, even though insulin concentrations are increased because of insulin resistance secondary to GH action.91 GH excess in children and adolescents prior to closure of the growth plate of the long bones results in continued growth (gigantism). In adults, GH excess causes acromegaly (acral overgrowth). Acromegaly occurs with GH-secreting pituitary tumors and rarely with ectopic production of growth hormone-releasing hormone, usually by bronchial carcinoids or pancreatic neuroendocrine tumors. Even though GH stimulates IGF-1 secretion and IGF-1 levels are elevated in acromegaly, GH excess is potentially diabetogenic. The actions of GH to mobilize FFAs, stimulate gluconeogenesis, and inhibit insulin action may lead to impaired fasting glucose (30%) and frank diabetes mellitus (16%) in acromegaly.92

6.2 Cushing’s Syndrome, Glucocorticoids, and 11-β-Hydroxysteroid Dehydrogenase

Glucocorticoids were named for their ability to raise blood glucose.94 Excess glucocorticoid secretion or administration can lead to diabetes mellitus. Cushing’s syndrome results from excess endogenous glucocorticoid (cortisol) secretion from adrenal gland tumors; from pituitary or other tumors secreting excessive amounts of ACTH, which stimulates adrenal cortisol production; or from exogenously administered glucocorticoids used in the treatment of asthma or autoimmune disorders. Glucose intolerance and diabetes mellitus are common in Cushing’s syndrome, with frank diabetes or impaired glucose tolerance occurring in 50–90% of affected individuals. Cortisol is one of the counter-regulatory hormones and acts at many steps. One action is to increase the appetite, thereby increasing energy intake with an initial rise in blood glucose level. The lipogenic action of cortisol, to store nutrients in visceral fat tissue, contributes to insulin resistance. The major actions of cortisol, like those of growth hormone, lead to extrahepatic substrate mobilization. The lipolytic action of cortisol mobilizes energy from adipose tissue, providing precursors for increased hepatic glucose production.95 Cortisol antagonizes the effects of insulin in muscle, preventing protein synthesis and inhibiting glucose utilization; further, its catabolic actions include muscle breakdown,96 with the effect of delivering gluconeogenic precursors to the liver. In the liver, cortisol stimulates both gluconeogenesis and glycogen breakdown.

The pivotal role that cortisol may play in insulin resistance and type 2 diabetes mellitus is highlighted by observations that increased cortisol production in visceral fat can be shown in a transgenic mouse model to recreate the metabolic syndrome of insulin resistance, diabetes, and hypertension (Fig. 16.2).97 , 98

Fig. 16.2
figure 16_2_105153_2_En

Increased activity of 11-β-hydroxysteroid dehydrogenase type 1 in transgenic mice increases cortisol production in visceral fat and causes abdominal obesity and the metabolic syndrome resembling that seen in “apple-shaped” people99

Full size image

6.3 Pheochromocytoma

Pheochromocytomas, a general term applied to tumors of the adrenal medulla and the extra-adrenal chromaffin tissue, secrete catecholamines, especially norepinephrine. Headache related to extreme elevations of blood pressure (α1-adrenergic stimulation), palpitations (β1-adrenergic stimulation), anxiety, and diaphoresis dominates the clinical presentation. Diabetes occurs in up to 65% of pheochromocytomas, may mirror the paroxysmal rises in blood pressure, and has been demonstrated to resolve following tumor resection.100 Pheochromocytomas whose major secretory product is epinephrine are much more likely than norepinephrine-secreting tumors to present with arrhythmias, non-cardiac pulmonary edema, hypotension, and hyperglycemia. This distinct presentation reflects the combined α- and β-adrenergic stimulation of epinephrine (Fig. 16.3). The more common norepinephrine-secreting tumors may also cause hyperglycemia since norepinephrine is also a mixed agonist, although with less β activity than does epinephrine.101

Fig. 16.3
figure 16_3_105153_2_En

The coordinated actions of elevated epinephrine in pheochromocytoma raise blood glucose102

Full size image

6.4 Hyperthyroidism

Thyroid hormone increases glucose transporters 4 (GLUT-4) in fat tissue and muscle, thereby enhancing the stimulatory effect of insulin.103 Given the increase in metabolic rate caused by thyroid hormones, it is logical that increased fuel would be made available to tissues. It is paradoxical then that hyperthyroidism is sometimes associated with deterioration of glucose control or with onset of frank diabetes mellitus. Partial explanations implicate increased growth hormone secretion104; a hepatic gene expression profile that promotes gluconeogenesis and glycogenolysis, and decreases insulin action105; and increased hepatic GLUT-2 transporters, through which glucose effluxes out of the liver.106

6.5 Hyperaldosteronism

Primary hyperaldosteronism, the elevated secretion of the mineralocorticoid aldosterone resulting from adrenal cortical tumors, genetic mutations, or idiopathic hyperaldosteronism, is classified with the endocrinopathies that cause “other specific types” of diabetes mellitus.1 Yet, little is known about the occurrence, the mechanism, or the resolution of the glucose intolerance seen with hypersecretion of aldosterone. One retrospective study found a prevalence of diabetes of 5–24% in hyperaldosteronism.107 Physiologic potassium levels play a fundamental role in insulin secretion. Potassium stimulates glucose-induced insulin secretion, and insulin lowers serum potassium by driving the cation intracellularly.108 The hypokalemia that occurs with renal potassium wasting in primary aldosteronism presumably has a restraining or inhibiting effect on insulin secretion and leads to glucose intolerance and diabetes in susceptible individuals. In addition, insulin resistance may occur.109 The diabetes that occurs with hyperaldosteronism may (personal observation) or may not110 resolve with cure of hyperaldosteronism.

7 Conclusion

Diverse organs and drugs are implicated in secondary diabetes mellitus. Pancreatic destruction is treatable only with insulin replacement. The link between liver disease and diabetes is poorly understood. The lipodystrophy and metabolic consequences of HIV infection and its therapies are under active investigation. Sometimes medications that cause diabetes may be discontinued, but others are life saving and lack appropriate substitutions. Cure of the endocrinopathies that cause diabetes may ameliorate or cure the associated diabetes. Ultimately, the explanation for the mechanisms that cause secondary diabetes mellitus can be sought in the basic physiology and pathophysiology of the secretion of insulin and its action on target tissues.

8 Useful Websites