How should diabetes secondary to an underlying condition such as pancreatic disease, Cushing’s syndrome, chronic glucocorticoid therapy, haemochromatosis, or HIV infection be managed?

Management of Diabetes Secondary to Underlying Conditions

Diabetes caused by pancreatic disease, Cushing's syndrome, chronic glucocorticoid therapy, hemochromatosis, or HIV infection requires treating both the hyperglycemia and the underlying condition, with insulin as the preferred agent in most cases due to the severity of insulin deficiency or resistance in these contexts. 1, 2

General Principles

• The primary goal is to address the underlying condition whenever possible, as correction of the root cause (e.g., tumor removal in Cushing's syndrome, discontinuation of glucocorticoids when feasible) may normalize or significantly improve glucose metabolism. 1, 2

• Understanding the pathogenesis is more clinically important than labeling the diabetes type, as this guides treatment selection—for example, pancreatic diabetes involves both insulin deficiency and exocrine dysfunction, while glucocorticoid-induced diabetes primarily involves insulin resistance. 1

Pancreatic Diabetes (Pancreoprivic Diabetes)

Pathophysiology and Recognition

• Pancreatic diabetes results from structural and functional loss of insulin secretion combined with exocrine pancreatic dysfunction, commonly misdiagnosed as type 2 diabetes. 1

• Even a single episode of acute pancreatitis can cause postpancreatitis diabetes mellitus (PPDM), with both acute and chronic pancreatitis leading to this complication. 1

• Etiologies include pancreatitis, trauma, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis, and fibrocalculous pancreatopathy. 1

Treatment Approach

• Insulin therapy is typically required due to the absolute or near-absolute insulin deficiency from β-cell destruction. 1

• Monitor for exocrine pancreatic insufficiency and provide pancreatic enzyme replacement therapy when indicated, as this affects nutrient absorption and glycemic control. 1

• Screen for malabsorption and nutritional deficiencies that commonly accompany pancreatic disease and can complicate diabetes management. 1

Cushing's Syndrome and Glucocorticoid-Induced Diabetes

Pathophysiology

• Glucocorticoid excess causes diabetes through multiple mechanisms: stimulation of hepatic gluconeogenesis, inhibition of insulin sensitivity in liver and skeletal muscle, impaired insulin secretion from pancreatic β-cells, and promotion of visceral adiposity. 2, 3

• The progression from impaired glucose tolerance to overt diabetes occurs when glucocorticoid-induced insulin resistance overwhelms the pancreatic β-cell compensatory capacity. 3

Management Strategy

• Surgical or medical treatment of endogenous Cushing's syndrome is the definitive therapy, as correction of hypercortisolism may reverse hyperglycemia. 2

• For exogenous glucocorticoid therapy, reduce the dose or discontinue when medically feasible, though many patients require continued glucocorticoid treatment for their underlying condition. 1

• When glucocorticoids cannot be discontinued, insulin-sensitizing agents (metformin, thiazolidinediones) are preferred initial therapy to address the primary mechanism of insulin resistance. 1, 2

• Insulin therapy should be initiated when oral agents fail to achieve glycemic targets or when hyperglycemia is severe (>250 mg/dL). 4, 2

• Important caveat: If glucocorticoids are discontinued after diabetes develops, the patient may become normoglycemic temporarily but can develop diabetes years later, indicating that glucocorticoids may unmask underlying predisposition to type 2 diabetes rather than solely causing it. 1

HIV-Associated Diabetes

Screening Protocol

• Screen with fasting glucose every 6-12 months before starting antiretroviral therapy (ART), then 3 months after starting or changing ART, then annually if initial results are normal. 1

• Do not use A1C for diagnosis in HIV patients, as it underestimates glycemia in this population and presents challenges for monitoring. 1

Risk Factors and Pathophysiology

• Protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) increase diabetes risk, with new-onset diabetes occurring in >5% of patients on PIs and prediabetes in >15%. 1

• PIs cause insulin resistance and may induce pancreatic β-cell apoptosis, while NRTIs affect fat distribution (lipohypertrophy and lipoatrophy), which is associated with insulin resistance. 1

• HIV-HCV coinfection increases diabetes risk 5-fold compared to HIV alone. 1

Treatment Approach

• Consider switching to alternative ART regimens if safe and effective options exist that do not promote hyperglycemia, carefully weighing the impact on HIV virological control. 1

• For prediabetes, implement intensive lifestyle interventions focusing on weight loss through healthy nutrition and physical activity to reduce progression to diabetes. 1

• When antihyperglycemic agents are needed, insulin-sensitizing agents (metformin, thiazolidinediones) are preferred to address the insulin resistance mechanism. 1

• Manage according to standard diabetes guidelines with aggressive cardiovascular risk factor modification, as preventive care similar to non-HIV patients is critical to reduce microvascular and macrovascular complications. 1

Hemochromatosis-Related Diabetes

• Hemochromatosis causes pancreatic diabetes through iron deposition in pancreatic β-cells, leading to insulin deficiency. 1

• Therapeutic phlebotomy or chelation therapy to reduce iron overload is essential, though diabetes may not fully resolve even with adequate iron reduction. 1

• Insulin therapy is often required due to the degree of β-cell destruction from chronic iron toxicity. 1

Common Pitfalls to Avoid

• Do not assume these patients have typical type 2 diabetes and can be managed with standard oral agents alone—many require insulin due to significant insulin deficiency or severe insulin resistance. 1

• Never discontinue insulin in patients with pancreatic diabetes or severe glucocorticoid-induced diabetes, as this can precipitate life-threatening hyperglycemic crisis. 5, 4

• Avoid using sliding-scale insulin as monotherapy, as this approach is ineffective and leads to wide glucose fluctuations; use basal-bolus regimens instead. 4

• Do not overlook the underlying condition—failure to treat Cushing's syndrome, switch problematic ART, or provide pancreatic enzyme replacement will result in suboptimal diabetes control. 1, 2

• In HIV patients, do not rely on A1C for diagnosis or monitoring—use fasting glucose and consider continuous glucose monitoring when available. 1

Patient-Centered Considerations

• Engage patients in shared decision-making regarding treatment choices, particularly when considering ART switches in HIV patients or glucocorticoid dose adjustments, as these decisions affect both the underlying condition and diabetes management. 1

• Provide diabetes self-management education tailored to the specific underlying condition, including sick-day management, medication adherence, and recognition of hyperglycemic emergencies. 5, 4

• Implement multifactorial cardiovascular risk reduction including blood pressure control (<130/80 mmHg), statin therapy for lipid management, and antiplatelet therapy when indicated, as these patients face elevated cardiovascular risk. 1, 6