Type 2 diabetes mellitus caused by Gitelman syndrome-related hypokalemia

Abstract

Introduction: Gitelman syndrome (GS) is an autosomal-recessive disease caused by SLC12A3 gene mutations. It is characterized by hypokalemic metabolic alkalosis in combination with hypomagnesemia and hypocalciuria. Recently, patients with GS are found at an increased risk for developing type 2 diabetes mellitus (T2DM). However, diagnosis of hyperglycemia in GS patients has not been thoroughly investigated, and family studies on SLC12A3 mutations and glucose metabolism are rare. Whether treatment including potassium and magnesium supplements, and spironolactone can ameliorate impaired glucose tolerance in GS patients, also needs to be investigated. Patient concerns: We examined a 55-year-old Chinese male with intermittent fatigue and persistent hypokalemia for 17 years. Diagnoses: Based on the results of the clinical data, including electrolytes, oral glucose tolerance test (OGTT), and genetic analysis of the SLC12A3 gene, GS and T2DM were newly diagnosed in the patient. Two mutations of the SLC12A3 gene were found in the patient, one was a missense mutation p.N359K in exon 8, and the other was a novel insert mutation p.I262delinsIIGVVSV in exon 6. SLC12A3 genetic analysis and OGTT of 9 other family members within 3 generations were also performed. Older brother, youngest sister, and son of the patient carried the p.N359K mutation in exon 8. The older brother and the youngest sister were diagnosed with T2DM and impaired glucose tolerance by OGTT, respectively. Interventions: The patient was prescribed potassium and magnesium (potassium magnesium aspartate, potassium chloride) oral supplements and spironolactone. The patient was also suggested to maintain a high potassium diet. Acarbose was used to maintain the blood glucose levels. Outcomes: The electrolyte imbalance including hypokalemia and hypomagnesemia, and hyperglycemia were improved with a remission of the clinical manifestations. Conclusion: GS is one of the causes for manifestation of hypokalemia. SLC12A3 genetic analysis plays an important role in diagnosis of GS. Chinese male GS patients characterized with heterozygous SLC12A3 mutation should be careful toward occurrence of T2DM. Moreover, the patients with only 1 SLC12A3 mutant allele should pay regular attention to blood potassium and glucose levels. GS treatment with potassium and magnesium supplements, and spironolactone can improve impaired glucose metabolism.

Gitelman syndrome with a novel frameshift variant in SLC12A3 gene accompanied by chronic kidney disease and type 2 diabetes mellitus

“…As noted above, Gitelman syndrome is often associated with diabetes mellitus [14,16,18,19]. Abnormal glucose tolerance may be caused by increased insulin resistance and decreased insulin secretion due to hypomagnesemia and hypokalemia [14,18,23].…”

“…The patient had hypokalemia, hypomagnesemia, and hypocalciuria, which are typical laboratory findings of Gitelman syndrome. Impaired renal function, proteinuria, and diabetes mellitus-relatively common complications of Gitelman syndrome [12][13][14][15][16][17][18][19]-were also observed. In a study from Taiwan, seven out of forty patients with Gitelman syndrome had CKD, and five out of forty patients had diabetes [16].…”

Case report: Gitelman syndrome with diabetes: Confirmed by both hydrochlorothiazide test and genetic testing

“…[15] In Table 3, We summarized the general characteristics of GS patients with T2DM in published articles. [21–26] Based on the results, the mutation sites in GS patients with T2DM are mostly located in the exon areas, and it is more common in Chinese male patients. Some patients were diagnosed with T2DM earlier than GS, so it is not clear whether the cause of T2DM in these patients is caused by GS.…”

Hypokalemia in Diabetes Mellitus Setting

“…Importantly, Gitelman´s syndrome patients may be at greater risk of developing insulin resistance and type 2 DM [ 34 ], as chronic hypokalemia and hypomagnesemia impair insulin secretion and sensitivity, whereas hyperaldosteronism increases insulin resistance. From a molecular and cellular point of view, when glucose enters the pancreatic ß cell via GLUT2 transporter, it is metabolized to glucose-6-phosphate leading to changes in the intracellular concentration of adenine nucleotides that inhibit the K ATP channel and cause its closure.…”