Diagnosis and Treatment > Medication > DPP4 inhibitors
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Department of Internal Medicine, Keiju Medical Center, Nanao, Ishikawa, Japan
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Department of Health Promotion and Medicine of the Future, Kanazawa University, Kanazawa, Ishikawa, Japan
Search for other papers by Takashi Yoneda in
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Search for other papers by Yoshiyu Takeda in
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Summary
Renovascular hypertension (RVHT) is an important and potentially treatable form of resistant hypertension. Hypercortisolemia could also cause hypertension and diabetes mellitus. We experienced a case wherein adrenalectomy markedly improved blood pressure and plasma glucose levels in a patient with RVHT and low-level autonomous cortisol secretion. A 62-year-old Japanese man had been treated for hypertension and diabetes mellitus for 10 years. He was hospitalized because of a disturbance in consciousness. His blood pressure (BP) was 236/118 mmHg, pulse rate was 132 beats/min, and plasma glucose level was 712 mg/dL. Abdominal CT scanning revealed the presence of bilateral adrenal masses and left atrophic kidney. Abdominal magnetic resonance angiography demonstrated marked stenosis of the left main renal artery. The patient was subsequently diagnosed with atherosclerotic RVHT with left renal artery stenosis. His left adrenal lobular mass was over 40 mm and it was clinically suspected the potential for cortisol overproduction. Therefore, laparoscopic left nephrectomy and adrenalectomy were simultaneously performed, resulting in improved BP and glucose levels. Pathological studies revealed the presence of multiple cortisol-producing adrenal nodules and aldosterone-producing cell clusters in the adjacent left adrenal cortex. In the present case, the activated renin-angiotensin-aldosterone system and cortisol overproduction resulted in severe hypertension, which was managed with simultaneous unilateral nephrectomy and adrenalectomy.
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Concomitant activation of the renin-angiotensin-aldosterone system and cortisol overproduction may contribute to the development of severe hypertension and lead to lethal cardiovascular complications.
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Treatment with simultaneous unilateral nephrectomy and adrenalectomy markedly improves BP and blood glucose levels.
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CYP11B2 immunohistochemistry staining revealed the existence of aldosterone-producing cell clusters (APCCs) in the adjacent non-nodular adrenal gland, suggesting that APCCs may contribute to aldosterone overproduction in patients with RVHT.
Search for other papers by Diana Catarino in
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Search for other papers by Leonor Gomes in
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Summary
Pituitary infections, particularly with fungus, are rare disorders that usually occur in immunocompromised patients. Cushing’s syndrome predisposes patients to infectious diseases due to their immunosuppression status. We report the case of a 55-year-old woman, working as a poultry farmer, who developed intense headache, palpebral ptosis, anisocoria, prostration and psychomotor agitation 9 months after initial diabetes mellitus diagnosis. Cranioencephalic CT scan showed a pituitary lesion with bleeding, suggesting pituitary apoplexy. Patient underwent transsphenoidal surgery and the neuropathologic study indicated a corticotroph adenoma with apoplexy and fungal infection. Patient had no preoperative Cushing’s syndrome diagnosis. She was evaluated by a multidisciplinary team who decided not to administer anti-fungal treatment. The reported case shows a rare association between a corticotroph adenoma and a pituitary fungal infection. The possible contributing factors were hypercortisolism, uncontrolled diabetes and professional activity. Transsphenoidal surgery is advocated in these infections; however, anti-fungal therapy is still controversial.
Learning points:
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Pituitary infections are rare disorders caused by bacterial, viral, fungal and parasitic infections.
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Pituitary fungal infections usually occur in immunocompromised patients.
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Cushing’s syndrome, as immunosuppression factor, predisposes patients to infectious diseases, including fungal infections.
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Diagnosis of pituitary fungal infection is often achieved during histopathological investigation.
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Treatment with systemic anti-fungal drugs is controversial.
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Endocrine evaluation is recommended at the time of initial presentation of pituitary manifestations.
Search for other papers by Ana Gonçalves Ferreira in
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Search for other papers by Tiago Nunes da Silva in
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Search for other papers by Sofia Alegria in
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Search for other papers by Maria Carlos Cordeiro in
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Summary
Pheochromocytoma/paraganglioma (PPGL) are neuroendocrine tumors that can secrete catecholamines. The authors describe a challenging case who presented as stress cardiomyopathy and myocardial infarction (MI). A 76-year-old man, with a medical history of Parkinson’s disease, type 2 diabetes mellitus, hypertension, dyslipidaemia and a previous inferior MI in 2001, presented to the emergency department due to chest pain, headaches and vomiting. He also reported worsening blood glucose levels and increasing constipation over the preceding weeks. BP was 185/89 mmHg (no other relevant findings). EKG had ST segment depression in leads V2-V6, T troponin was 600 ng/L (<14) and the echocardiogram showed left ventricular hypokinesia with mildly compromised systolic function. Nevertheless, he rapidly progressed to severe biventricular dysfunction. Coronary angiogram showed a 90% anterior descendent coronary artery occlusion (already present in 2001), which was treated with angioplasty/stenting. In the following days, a very labile BP profile and unexplained sinus tachycardia episodes were observed. Because of sustained severe constipation, the patient underwent an abdominal CT that revealed a retroperitoneal, heterogeneous, hypervascular mass on the right (62 × 35 mm), most likely a paraganglioma. Urinary metanephrines were increased several fold. 68Ga-DOTANOC PET-CT scan showed increased uptake in the abdominal mass (no evidence of disease elsewhere). He was started on a calcium-channel blocker and alpha blockade and underwent surgery with no major complications. Eight months after surgery, the patient has no evidence of disease. Genetic testing was negative for known germline mutations. This was a challenging diagnosis, but it was essential for adequate cardiovascular stabilization and to reduce further morbidity.
Learning points:
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PPGL frequently produces catecholamines and can manifest with several cardiovascular syndromes, including stress cardiomyopathy and myocardial infarction.
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Even in the presence of coronary artery disease (CAD), PPGL should be suspected if signs or symptoms attributed to catecholamine excess are present (in this case, high blood pressure, worsening hyperglycaemia and constipation).
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Establishing the correct diagnosis is important for adequate treatment choice.
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Inodilators and mechanical support might be preferable options (if available) for cardiovascular stabilization prior to alpha blockade and surgery.
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Laboratory interference should be suspected irrespective of metanephrine levels, especially in the context of treated Parkinson’s disease.
Search for other papers by Michelle Maher in
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HRB Clinical Research Facility, National University of Ireland Galway, Galway, Ireland
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HRB Clinical Research Facility, National University of Ireland Galway, Galway, Ireland
Search for other papers by Francis M Finucane in
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Summary
A 45-year-old man with poorly controlled type 2 diabetes (T2DM) (HbA1c 87 mmol/mol) despite 100 units of insulin per day and severe obesity (BMI 40.2 kg/m2) was referred for bariatric intervention. He declined bariatric surgery or GLP1 agonist therapy. Initially, his glycaemic control improved with dietary modification and better adherence to insulin therapy, but he gained weight. We started a low-energy liquid diet, with 2.2 L of semi-skimmed milk (equivalent to 1012 kcal) per day for 8 weeks (along with micronutrient, salt and fibre supplementation) followed by 16 weeks of phased reintroduction of a normal diet. His insulin was stopped within a week of starting this programme, and over 6 months, he lost 20.6 kg and his HbA1c normalised. However, 1 year later, despite further weight loss, his HbA1c deteriorated dramatically, requiring introduction of linagliptin and canagliflozin, with good response. Five years after initial presentation, his BMI remains elevated but improved at 35.5 kg/m2 and his glycaemic control is excellent with a HbA1c of 50 mmol/mol and he is off insulin therapy. Whether semi-skimmed milk is a safe, effective substrate for carefully selected patients with severe obesity complicated by T2DM remains to be determined. Such patients would need frequent monitoring by an experienced multidisciplinary team.
Learning points:
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Meal replacement programmes are an emerging therapeutic strategy to allow severely obese type 2 diabetes patients to achieve clinically impactful weight loss.
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Using semi-skimmed milk as a meal replacement substrate might be less costly than commercially available programmes, but is likely to require intensive multidisciplinary bariatric clinical follow-up.
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For severely obese adults with poor diabetes control who decline bariatric surgery or GLP1 agonist therapy, a milk-based meal replacement programme may be an option.
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Milk-based meal replacement in patients with insulin requiring type 2 diabetes causes rapid and profound reductions in insulin requirements, so rigorous monitoring of glucose levels by patients and their clinicians is necessary.
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In carefully selected and adequately monitored patients, the response to oral antidiabetic medications may help to differentiate between absolute and relative insulin deficiency.
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Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia
Search for other papers by Peter R Ebeling in
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Summary
We report a case of a 67-year-old man with type 2 diabetes presented with diabetic ketoacidosis, two weeks after his first dose of nivolumab therapy for non–small-cell lung carcinoma. He was started on empagliflozin two days prior in the setting of hyperglycaemia after the initiation of nivolumab therapy. Laboratory evaluation revealed an undetectable C-peptide and a positive anti-glutamic acid decarboxylase (GAD) antibody. He was treated with intravenous fluids and insulin infusion and was subsequently transitioned to subcutaneous insulin and discharged home. He subsequently has developed likely autoimmune thyroiditis and autoimmune encephalitis.
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Glycemic surveillance in patients receiving immune checkpoint inhibitors is recommended.
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Early glycemic surveillance after commencement of anti-programmed cell death-1 (PD-1) inhibitors may be indicated in selected populations, including patients with underlying type 2 diabetes mellitus and positive anti-glutamic acid decarboxylase (GAD) antibody.
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Sodium-glucose co transporter-2 (SGLT2) inhibitors should be used with caution in patients on immunotherapy.
Search for other papers by Ken Takeshima in
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Search for other papers by Takashi Akamizu in
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Summary
Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystem disease affecting muscles, the eyes and the endocrine organs. Diabetes mellitus and primary hypogonadism are endocrine manifestations typically seen in patients with DM1. Abnormalities of hypothalamic–pituitary–adrenal (HPA) axis have also been reported in some DM1 patients. We present a case of DM1 with a rare combination of multiple endocrinopathies; diabetes mellitus, a combined form of primary and secondary hypogonadism, and dysfunction of the HPA axis. In the present case, diabetes mellitus was characterized by severe insulin resistance with hyperinsulinemia. Glycemic control improved after modification of insulin sensitizers, such as metformin and pioglitazone. Hypogonadism was treated with testosterone replacement therapy. Notably, body composition analysis revealed increase in muscle mass and decrease in fat mass in our patient. This implies that manifestations of hypogonadism could be hidden by symptoms of myotonic dystrophy. Our patient had no symptoms associated with adrenal deficiency, so adrenal dysfunction was carefully followed up without hydrocortisone replacement therapy. In this report, we highlight the necessity for evaluation and treatment of multiple endocrinopathies in patients with DM1.
Learning points:
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DM1 patients could be affected by a variety of multiple endocrinopathies.
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Our patients with DM1 presented rare combinations of multiple endocrinopathies; diabetes mellitus, combined form of primary and secondary hypogonadism and dysfunction of HPA axis.
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Testosterone treatment of hypogonadism in patients with DM1 could improve body composition.
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The patients with DM1 should be assessed endocrine functions and treated depending on the degree of each endocrine dysfunction.
Search for other papers by Elena Carrillo in
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Search for other papers by Cristina Lamas in
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Summary
Mutations in hepatocyte nuclear factor 1β gene (HNF1B) are responsible for a multisystemic syndrome where monogenic diabetes (classically known as MODY 5) and renal anomalies, mostly cysts, are the most characteristic findings. Urogenital malformations, altered liver function tests, hypomagnesemia or hyperuricemia and gout are also part of the syndrome. Diabetes in these patients usually requires early insulinization. We present the case of a young non-obese male patient with a personal history of renal multicystic dysplasia and a debut of diabetes during adolescence with simple hyperglycemia, negative pancreatic autoimmunity and detectable C-peptide levels. He also presented epididymal and seminal vesicle cysts, hypertransaminasemia, hyperuricemia and low magnesium levels. In the light of these facts we considered the possibility of a HNF1B mutation. The sequencing study of this gene confirmed a heterozygous mutation leading to a truncated and less functional protein. Genetic studies of his relatives were negative; consequently, it was classified as a de novo mutation. In particular, our patient maintained good control of his diabetes on oral antidiabetic agents for a long period of time. He eventually needed insulinization although oral therapy was continued alongside, allowing reduction of prandial insulin requirements. The real prevalence of mutations in HNF1B is probably underestimated owing to a wide phenotypical variability. As endocrinologists, we should consider this possibility in young non-obese diabetic patients with a history of chronic non-diabetic nephropathy, especially in the presence of some of the other characteristic manifestations.
Learning points:
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HNF1B mutations are a rare cause of monogenic diabetes, often being a part of a multisystemic syndrome.
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The combination of young-onset diabetes and genitourinary anomalies with slowly progressive nephropathy of non-diabetic origin in non-obese subjects should rise the suspicion of such occurrence. A family history may not be present.
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Once diagnosis is made, treatment of diabetes with oral agents is worth trying, since the response can be sustained for a longer period than the one usually described. Oral treatment can help postpone insulinization and, once this is necessary, can help reduce the required doses.
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Summary
Long-acting pasireotide is an effective treatment option for acromegaly, but it is associated with hyperglycemia, which could impact its use in patients with diabetes. We present a case of a 53-year-old man with acromegaly and type 2 diabetes mellitus (glycated hemoglobin (HbA1c): 7.5%), who refused surgery to remove a pituitary macroadenoma and enrolled in a Phase 3 clinical trial comparing long-acting pasireotide and long-acting octreotide in acromegalic patients. The patient initially received octreotide, but insulin-like growth factor 1 (IGF-1) levels remained elevated after 12 months (383.9 ng/mL; 193.0 ng/mL; reference range: 86.5–223.8 ng/mL), indicating uncontrolled acromegaly. He switched to pasireotide 40 mg and subsequently increased to 60 mg. Within 6 months, IGF-1 levels normalized (193.0 ng/mL), and they were mostly normal for the next 62 months of treatment with pasireotide (median IGF-1: 190.7 ng/mL). Additionally, HbA1c levels remained similar to or lower than baseline levels (range, 6.7% to 7.8%) during treatment with pasireotide despite major changes to the patient’s antidiabetic regimen, which included insulin and metformin. Uncontrolled acromegaly can result in hyperglycemia due to an increase in insulin resistance. Despite having insulin-requiring type 2 diabetes, the patient presented here did not experience a long-term increase in HbA1c levels upon initiating pasireotide, likely because long-term control of acromegaly resulted in increased insulin sensitivity. This case highlights the utility of long-acting pasireotide to treat acromegaly in patients whose levels were uncontrolled after long-acting octreotide and who manage diabetes with insulin.
Learning points
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Long-acting pasireotide provided adequate, long-term biochemical control of acromegaly in a patient with insulin-requiring type 2 diabetes mellitus who was unresponsive to long-acting octreotide.
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Glycemic levels initially increased after starting treatment with pasireotide but quickly stabilized as acromegaly became controlled.
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Long-acting pasireotide, along with an appropriate antidiabetic regimen, may be a suitable therapy for patients with acromegaly who also have insulin-requiring type 2 diabetes mellitus.
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Search for other papers by Felipe Moura Maia Pinheiro in
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Search for other papers by Margareth Afonso Torres in
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Summary
Type 1 diabetes mellitus (T1DM) is a chronic disease characterized by autoimmune destruction of pancreatic beta cells and inadequate insulin production. Remission criteria in T1DM take into account serum levels of C-peptide and glycosylated hemoglobin, as well as the dose of insulin administered to the patient. However, remission of T1DM lasting longer than 1 year is rare. We describe here the cases of two young women who presented with positive glutamic acid decarboxylase (GAD) antibody and classic clinical manifestations of T1DM. Both patients had a prior history of Hashimoto’s thyroiditis. They were initially treated with a basal-bolus regimen of insulin (glargine and lispro/glulisine). Once their blood glucose levels were controlled, they were started on oral sitagliptin 100 mg and vitamin D3 5000 IU daily. After this therapy, both patients achieved clinical diabetes remission for 4 years, along with a decrease in anti-GAD antibody levels. These benefits were probably associated with immunological effects of these medications. Inhibition of dipeptidyl peptidase 4 (DPP-4) in animal models deregulates Th1 immune response, increases secretion of Th2 cytokines, activates CD4+CD25+FoxP3+ regulatory T-cells and prevents IL-17 production. Vitamin D3 also activates CD4+CD25+FoxP3+ regulatory T-cells, and these medications combined can improve the immune response in patients with new-onset T1DM and probably promote sustained clinical remission.
Learning points:
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The use of sitagliptin and vitamin D3 in patients with new-onset type 1 diabetes mellitus (T1DM) may help decrease the daily insulin requirement by delaying beta cell loss and improving endogenous insulin production.
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The use of sitagliptin and vitamin D3 in new-onset T1DM could help regulate the imbalance between Th17 and Treg cells.
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Age 14 years or above, absence of ketoacidosis and positive C-peptide levels in patients with T1DM are good criteria to predict prolonged T1DM remission.
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The determination of anti-GAD antibodies and C-peptide levels could be helpful in the follow-up of patients in use of sitagliptin and vitamin D3, which could be associated with prolonged T1DM clinical remission.
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Summary
Latent autoimmune diabetes in adults (LADA) is a relatively new type of diabetes with a clinical phenotype of type 2 diabetes (T2D) and an immunological milieu characterized by high titers of islet autoantibodies, resembling the immunological profile of type 1 diabetes (T1D). Herein, we report a case of a young male, diagnosed with LADA based on both clinical presentation and positive anti-glutamic acid decarboxylase antibodies (GAD-abs), which were normalized after combined treatment with a dipeptidyl peptidase-4 inhibitor (DPP-4) (sitagliptin) and cholecalciferol.
Learning points
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Anti-glutamic acid decarboxylase antibodies (GAD-abs) titers in young patients being previously diagnosed as type 2 diabetes (T2D) may help establish the diagnosis of latent autoimmune diabetes in adults (LADA).
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Sitagliptin administration in patients with LADA might prolong the insulin-free period.
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Vitamin D administration in patients with LADA might have a protective effect on the progression of the disease.
