Metformin-associated Lactic Acidosis with Hypoglycemia during the COVID-19 Pandemic.

Metformin-associated lactic acidosis (MALA) is an extremely rare but life-threatening adverse effect of metformin treatment. The lifestyle changes associated with the coronavirus disease 2019 (COVID-19) pandemic may increase the potential risk of MALA development in patients with diabetes. We herein report a 64-year-old Japanese man taking a small dose of metformin who presented with MALA accompanied by hypoglycemia secondary to increased alcohol consumption triggered by lifestyle changes during the pandemic. Physicians should prescribe metformin judiciously to prevent MALA development and pay close attention to lifestyle changes in patients at risk for MALA during the COVID-19 pandemic.

Coexistence of Renin-independent Aldosterone Secretion and Multiple Endocrine Neoplasia Type 1 Within a Family.

Primary aldosteronism (PA) is a state of renin-independent aldosterone secretion that can range from subclinical to overt. Some normotensive individuals for whom PA screening is not routinely recommended are reported to fulfill the loading test criterion used for the diagnosis of PA. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the development of various endocrine tumors. Cases of PA associated with MEN1 have been reported; however, there has been no previous report on renin-independent aldosterone secretion within a family with MEN1. Herein, we present the case of a normotensive family presenting with both MEN1 and renin-independent aldosterone secretion. A 49-year-old man was admitted to our hospital for PA evaluation owing to the plasma aldosterone concentration/plasma renin activity ratio being greater than the screening cut-off value; the patient was normotensive. The patient had a history of left nephrectomy and adrenalectomy for left renal carcinoma and adrenal tumor at the age of 39 years. Subsequently, he was diagnosed with MEN1 concurrent with primary hyperparathyroidism, insulinoma, and novel MEN1 gene mutations (c.655-5_655-4insC and c.818delC). The loading tests for PA confirmation, including saline infusion, and furosemide upright and captopril challenge tests, yielded positive findings, confirming a case of renin-independent aldosterone secretion. The patient's mother, brother, and sister were also genetically or clinically diagnosed with MEN1. All of them were also normotensive and confirmed to have renin-independent aldosterone secretion. The coexistence of renin-independent aldosterone secretion and MEN1 within this family suggests a relationship between the 2 entities.

Medium-term Influence of the Coronavirus Disease 2019 Pandemic on Patients with Diabetes: A Single-center Cross-sectional Study.

Objective This study evaluated the lifestyle changes in patients with diabetes and their independent associations with glycemic and body weight control. In addition, the correlation between changes in mental health and lifestyles was evaluated. Methods This single-center cross-sectional study included 340 patients with diabetes who periodically visited our department. Changes in dietary habits, activities of daily living, and mental health before and during approximately six months after the onset of the coronavirus disease 2019 (COVID-19) pandemic were evaluated using a questionnaire, including the International Physical Activity Questionnaire-Short Form. Results Approximately 20%, 30%, and over 50% of patients had worsened dietary habits, decreased activities of daily living, and deteriorated mental health, respectively. A multiple regression analysis showed that irregular meal timing was significantly associated with change in HbA1c (ß=0.328, p=0.001), and decreased walking time was significantly associated with changes in body weight (ß=-0.245, p=0.025). The change in fear and anxiety was positively associated with changes in meal timing regularity (r=0.129, p=0.019) and carbohydrate consumption (r=0.127, p=0.021). Subsequently, the change in depressed mood was positively associated with changes in carbohydrate (r=0.142, p=0.010) and alcohol (r=0.161, p=0.037) consumption, and the change in psychological stress was positively associated with changes in carbohydrates (r=0.183, p=0.001) and snack (r=0.151, p=0.008) consumption as well as sedentary time (r=0.158, p=0.004). Conclusion The COVID-19 pandemic has had a considerable medium-term impact on the lifestyle and mental health of patients with diabetes. Lifestyle changes were associated with glycemic and body weight control, and mental health changes were associated with lifestyle changes. These findings may provide important information on diabetes care during the pandemic.

Case of slowly progressive type 1 diabetes mellitus with drastically reduced insulin secretory capacity after immune checkpoint inhibitor treatment for advanced renal cell carcinoma.

We encountered a 55-year-old Japanese man with advanced renal cell carcinoma and slowly progressive type 1 diabetes mellitus (SPT1DM), whose insulin secretory capacity was drastically reduced for a brief period after only one cycle of immune checkpoint inhibitor (ICI) treatment. The patient had been diagnosed with type 2 diabetes at the age of 53 years and was treated using oral hypoglycemic agents. However, 2 years later, he was diagnosed with SPT1DM and autoimmune thyroiditis, based on the presence of anti-glutamic acid decarboxylase antibodies (GADA) and thyroid autoantibodies, which was accompanied by advanced renal cell carcinoma. At that time, his insulin secretory capacity was preserved (CPR 2.36 ng/mL), and good glycemic control was maintained using only medical nutrition therapy (HbA1c 6.3%). He subsequently developed destructive thyroiditis approximately 2 weeks after the first cycle of ICI treatment using nivolumab (a programmed cell death-1 inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated antigen-4 inhibitor) for advanced renal cell carcinoma. Three weeks later, his plasma glucose level markedly increased, and we detected absolute insulin deficiency and hypothyroidism. Human leukocyte antigen (HLA) analysis revealed haplotypes indicating susceptibility to type 1 diabetes mellitus (T1DM) or autoimmune thyroiditis (HLA genotype, DRB1-DQB1 *09:01-*03:03/*08:03-*06:01). He showed a good antitumor response and is currently receiving permanent insulin therapy and levothyroxine replacement with the ICI treatment. Based on this case and the available literature, patients with preexisting islet autoantibodies or SPT1DM/LADA, plus a genetic predisposition to T1DM, may have an extremely high risk of developing ICI-related T1DM for a brief period after starting ICI treatment.

Hypoglycemia during the Concomitant Use of Repaglinide and Clopidogrel in an Elderly Patient with Type 2 Diabetes and Severe Renal Insufficiency.

Hypoglycemia should be avoided when treating patients with diabetes. Repaglinide is an insulin secretagogue with a low hypoglycemic risk because of its rapid- and short-acting effects. However, its blood concentration has been reported to increase in combination with clopidogrel, an antiplatelet drug, and in patients with severe renal insufficiency. We herein report an elderly patient with type 2 diabetes mellitus and severe renal insufficiency who received repaglinide and hypoglycemia three days after starting clopidogrel. The concomitant use of repaglinide and clopidogrel can lead to hypoglycemia, especially in patients with severe renal insufficiency.

Beneficial effects of nateglinide on insulin resistance in type 2 diabetes.

Nateglinide, a rapid insulin secretagogue, is known to facilitate the early phase of insulin secretion and has been used for the treatment of type 2 diabetic patients with postprandial hyperglycemia. The aim of this study is to evaluate the effect of nateglinide on insulin resistance as well as insulin secretory defects in type 2 diabetic patients. Insulin secretion ability was evaluated by the hyperglycemic clamp test, and insulin sensitivity was evaluated by the euglycemic hyperinsulinemic clamp test, using an artificial pancreas. The hyperglycemic clamp test showed that a 7-day treatment with nateglinide significantly increased insulin secretion in response to high glucose. Interestingly, although nateglinide is known to facilitate insulin secretion, daily urinary C-peptide excretion was decreased after nateglinide treatment. Moreover, in the euglycemic hyperinsulinemic clamp test, glucose infusion rate was significantly increased by nateglinide treatment, indicating that nateglinide functions to decrease insulin resistance. Nateglinide ameliorates insulin resistance as well as insulin secretory defects in type 2 diabetic patients.

Hepatic insulin resistance induced by chronic hindlimb ischemia.

Peripheral vascular disease (PVD) has been reported to cause deterioration in insulin sensitivity. The precise mechanism of insulin resistance induced by PVD has not been clarified. To elucidate the mechanism causing impaired insulin action and glucose metabolism under peripheral ischemic conditions, we determined glucose turnover and glucose tolerance in hindlimb-ischemic (FAL) rats. The right femoral artery was ligated in hindlimb-ischemic (FAL) rats, while the artery was only exposed in the Sham operated (Sham) rats used as a control. Two weeks after the ligation, glucose tolerance was impaired and plasma insulin levels were significantly increased in FAL rats compared with Sham rats after intraperitoneal glucose loading (2 g kg(-1)). Under euglycemic hyperinsulinemic clamp conditions, the glucose infusion rate was significantly lower in FAL rats compared with Sham rats, but there was no significant difference in the glucose disappearance rate between the two groups. Hyperinsulinemia suppressed endogenous glucose production by 50% in Sham rats, while the suppression was 20% in FAL rats, indicating hepatic insulin resistance in FAL rats. mRNA analysis of isolated liver after the clamp experiment revealed that glucokinase mRNA, but not PEPCK and glucose-6-phosphatase mRNA, was significantly lower in FAL rats compared with Sham rats. In conclusion, chronic hindlimb ischemia impaired glucose tolerance associated with insulin resistance in the liver rather than the peripheral tissues.

Possible novel index determined by the glucose clamp test for selection of a suitable therapy for each type 2 diabetic patient.

The hallmark of type 2 diabetes is insulin resistance and insufficient insulin secretion, and appropriate therapy should be selected for each patient. In this study, to establish some index to select suitable therapy for each patient, we evaluated insulin sensitivity and insulin secretion with euglycemic hyperinsulinemic clamp and hyperglycemic clamp tests, respectively, and found that specific GIR index (GIRxIRI (90)) could be a useful marker to select suitable therapy for each type 2 diabetic patient (GIR: glucose infusion rate in euglycemic hyperinsulinemic clamp test; IRI (90): plasma insulin level 90 min after starting the hyperglycemic clamp test).

Insulin secretory defects and impaired islet architecture in pancreatic beta-cell-specific STAT3 knockout mice.

Normal islet formation and function depends on the action of various growth factors operating in pre- and postnatal development; however, the specific physiological function of each factor is largely unknown. Loss-of-function analyses in mice have provided little information so far, perhaps due to functional redundancies of the growth factors acting on the pancreas. The present study focuses on the role of the transcription factor STAT3 in insulin-producing cells. STAT3 is one of the potential downstream mediators for multiple growth factors acting on the pancreatic beta-cells, including betacellulin, hepatocyte growth factor, growth hormone, and heparin-binding EGF-like growth factor. To elucidate its role in the beta-cells, the STAT3 gene was disrupted in insulin-producing cells in mice (STAT3-insKO), using a cre-mediated gene recombination approach. Unexpectedly, STAT3-insKO mice exhibited an increase in appetite and obesity at 8 weeks of age or older. The mice showed partial leptin resistance, suggesting that expression of the RIP (rat insulin promoter)-cre transgene in hypothalamus partially inhibited the appetite-regulating system. Intraperitoneal glucose tolerance tests, performed in non-obese 5-week-old mice, showed that the STAT3-insKO mice were glucose intolerant. Islet perifusion experiments further revealed a deficiency in early-phase insulin secretion. Whereas islet insulin content or islet mass was not affected, expression levels of GLUT2, SUR1, and VEGF-A were significantly reduced in STAT3-insKO islets. Interestingly, STAT3-insKO mice displayed impaired islet morphology: alpha-cells were frequently seen in central regions of islets. Our present observations demonstrate a unique role of STAT3 in maintaining glucose-mediated early-phase insulin secretion and normal islet morphology.

Association of NAD(P)H oxidase p22 phox gene variation with advanced carotid atherosclerosis in Japanese type 2 diabetes.

OBJECTIVE: To evaluate the association between the C242T polymorphism of the p22 phox gene, an essential component of NAD(P)H oxidase in the vasculature, with intima-media thickness (IMT) of the carotid artery and risk factors for atherosclerosis in type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: C242T polymorphism of the p22 phox gene was detected by polymerase chain reaction-restriction fragment-length polymorphism in 200 Japanese type 2 diabetic subjects and 215 nondiabetic subjects. We examined the association with this mutation and carotid atherosclerosis as well as the patients' clinical characteristics and the level of 8-hydroxy-2'deoxyguanosine (8-OHdG) as an index of oxidative DNA damage. RESULTS: The diabetic subjects with the TC+TT genotypes displayed a significantly lower average IMT (1.13 +/- 0.31 vs. 1.31 +/- 0.34 mm; P = 0.0099) and a not significantly lower serum 8-OHdG level than those with the CC genotype, despite no difference in the risk factors. Stepwise multiple regression analysis showed that the risk factors for increased IMT in the diabetic subjects were systolic blood pressure (P = 0.0042) and p22 phox CC genotype (P = 0.0151). In nondiabetic subjects, the average IMT of the TC+TT group was not different from that of the CC group (0.85 +/- 0.14 vs. 0.94 +/- 0.30 mm, P = 0.417). Fasting plasma insulin concentration (41.4 +/- 15.6 vs. 64.2 +/- 59.4 pmol/l, P = 0.0098) and insulin resistance index of homeostasis model assessment (HOMA-R) (1.58 +/- 0.66 vs. 2.60 +/- 2.56, P = 0.0066) were significantly lower in the TC+TT group than in the CC group. CONCLUSIONS: These results show that the C242T mutation in the p22 phox gene is associated with progression of asymptomatic atherosclerosis in the subjects with type 2 diabetes and is also associated with insulin resistance in nondiabetic subjects.