Efficacy and Safety of Metreleptin Therapy in Patients With Type 1 Diabetes: A Pilot Study.

OBJECTIVE: To study the efficacy and safety of metreleptin therapy in patients with suboptimally controlled type 1 diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS: After a baseline period of 4 weeks, five female and three male patients with T1DM (mean age 33 years, BMI 23.8 kg/m2) received metreleptin (0.08 mg/kg/day in females and 0.04 mg/kg/day in males) subcutaneously twice daily for 20 weeks followed by an off-therapy period of 4 weeks. RESULTS: Metreleptin therapy did not lower HbA1c significantly compared with the baseline value (mean difference -0.19% [-2.0 mmol/mol] and -0.04% [-0.5 mmol/mol] at 12 and 20 weeks, respectively). Mean body weight reduced significantly by 2.6 and 4.7 kg (P = 0.003) and daily insulin dose by 12.6% and 15.0% at week 12 and 20 (P = 0.006), respectively. CONCLUSIONS: Metreleptin is safe but may not be efficacious in improving glycemic control in patients with T1DM, although it reduces body weight and daily insulin dose modestly.

Iatrogenic hyperinsulinemia in type 1 diabetes: its effect on atherogenic risk markers.

AIMS: Insulin is lipogenic and may invoke inflammation. We wished to determine if well controlled human and mice with type 1 diabetes had iatrogenic hyperinsulinemia as an explanation for the increased rate of coronary artery disease (CAD) in type 1 diabetes. METHODS: Type 1 diabetic subjects with HbA1C less than 7.0% had plasma insulin measured before and one hour after a Boost® challenge and a dose of subcutaneously administered insulin. These levels were compared with non-diabetic humans. Plasma insulin levels in well controlled NOD mice with type 1 diabetes were measured 3 h and 17 h after their usual dose of insulin. Hepatic cholesterol-relevant CAD and inflammation markers were measured in the NOD mice. RESULT: Marked iatrogenic hyperinsulinemia was observed in patients at levels of approximately two times higher than in non-diabetic controls. Similar findings were present in the NOD mice. Hepatic CAD risk markers were increased by insulin, but did not exceed normal expression levels in non-diabetic mice with lower insulin. In contrast, insulin-mediated stimulation of pro-inflammatory mediators TNF-α and IL-1ß remained significantly higher in hyperinsulinemic NOD than non-diabetic mice. CONCLUSION: Optimal insulin therapy in mice and humans with type 1 diabetes causes iatrogenic hyperinsulinemia and subsequently promotes pro-inflammatory macrophage response independent of hepatic cholesterol-relevant CAD markers. The tight glycemic control in type 1 diabetes may thus increase the risk for atherogenesis via inflammation.

Type 1 diabetes treatment beyond insulin: role of GLP-1 analogs.

OBJECTIVE: To observe the efficacy and safety of glucagonlike peptide-1 (GLP-1) analogs in type 1 diabetes in a real-life medical practice setting. METHODS: We performed a retrospective chart review of patients with type 1 diabetes initiated on a GLP-1 analog and with at least one follow-up visit at more than 4 weeks. RESULTS: We identified 11 patients who were initiated on a GLP-1 analog and had a follow-up visit between 4 and 13 weeks (mean (SD) follow-up 10 ± 3 weeks; age 36.5 ± 16.4 years; duration of diabetes 17.3 ± 9.3 years; all on insulin pump therapy; all started on liraglutide). Seven of these patients had a second follow-up visit at approximately 20 weeks. By 10 weeks, there was a significant decrease in weight (4.2% of total body weight), total daily insulin dose (19.2%, of which 14.0% basal and 24.1% bolus), and mean (SD) insulin units/kg (0.57 [0.17] to 0.48 [0.17] units/kg). Hemoglobin A1c was significantly decreased (7.4 [0.7%] to 7.0 [0.7%], P = 0.02) without an increase in hypoglycemia. These effects were sustained at 20 weeks. Nausea was a common adverse effect and lead to drug discontinuation in 4 of 11 patients. CONCLUSIONS: Patients with long-standing type 1 diabetes can achieve weight loss and improved glycemic control on less insulin without an increase in hypoglycemia when liraglutide is added to insulin therapy.

Leptin therapy in insulin-deficient type I diabetes.

In nonobese diabetic mice with uncontrolled type 1 diabetes, leptin therapy alone or combined with low-dose insulin reverses the catabolic state through suppression of hyperglucagonemia. Additionally, it mimics the anabolic actions of insulin monotherapy and normalizes hemoglobin A1c with far less glucose variability. We show that leptin therapy, like insulin, normalizes the levels of a wide array of hepatic intermediary metabolites in multiple chemical classes, including acylcarnitines, organic acids (tricarboxylic acid cycle intermediates), amino acids, and acyl CoAs. In contrast to insulin monotherapy, however, leptin lowers both lipogenic and cholesterologenic transcription factors and enzymes and reduces plasma and tissue lipids. The results imply that leptin administration may have multiple short- and long-term advantages over insulin monotherapy for type 1 diabetes.

Lipid homeostasis, lipotoxicity and the metabolic syndrome.

In the 20th century industrialized nations have become afflicted with an unprecedented pandemic of increased adiposity. In the United States, the epicenter of the epidemic, over 2/3 of the population, is overweight and 1 of every 6 Americans carries the diagnosis of metabolic syndrome. Although genes determine susceptibility to environmental factors, the epidemic is clearly due to increased consumption of calorie-dense, highly lipogenic foods, coupled with a marked decrease in physical exertion resulting from modern technologies. If this lifestyle continues, morbid consequences are virtually inevitable. They include type II diabetes and a cluster of disorders known as "the metabolic syndrome" usually appearing in middle age. The morbid consequences of the chronic caloric surplus are buffered before middle age by the partitioning of these calories as fat in the adipocyte compartment which is specifically designed to store triglycerides. Leptin has been proposed as the major hormonal regulator of the partitioning of surplus calories. However, multiple factors can determine the storage capacity of the fat tissue and when it is exceeded ectopic lipid deposition begins. The organs affected in metabolic syndrome include skeletal muscle, liver, heart and pancreas, which are now known to contain abnormal levels of triglycerides. While neutral fat is probably harmless, it is an index of ectopic lipid overload. Fatty acid derivatives can interfere with the function of the cell and ultimately lead to its demise through lipoapoptosis, the consequences of which are gradual organ failure.

Glucose responsive insulin production from human embryonic germ (EG) cell derivatives.

Type 1 diabetes mellitus subjects millions to a daily burden of disease management, life threatening hypoglycemia and long-term complications such as retinopathy, nephropathy, heart disease, and stroke. Cell transplantation therapies providing a glucose-regulated supply of insulin have been implemented clinically, but are limited by safety, efficacy and supply considerations. Stem cells promise a plentiful and flexible source of cells for transplantation therapies. Here, we show that cells derived from human embryonic germ (EG) cells express markers of definitive endoderm, pancreatic and beta-cell development, glucose sensing, and production of mature insulin. These cells integrate functions necessary for glucose responsive regulation of preproinsulin mRNA and expression of insulin C-peptide in vitro. Following transplantation into mice, cells become insulin and C-peptide immunoreactive and produce plasma C-peptide in response to glucose. These findings suggest that EG cell derivatives may eventually serve as a source of insulin producing cells for the treatment of diabetes.

Cell therapies for type 1 diabetes mellitus.

Type 1 diabetes is caused by autoimmune destruction of pancreatic beta-cells and is characterised by absolute insulin insufficiency. The monocellular nature of this disease and endocrine action of insulin make this disease an excellent candidate for cellular therapy. Furthermore, precedent for cellular therapies has been set by successful cadaveric whole pancreas and islet transplantation. In order to expand the supply of cells to meet current and future needs, several novel cell sources have been proposed, including human beta-cells or islets expanded in culture, islet xenografts and pancreatic ductal progenitor cells. Surrogate beta-cells derived from hepatocytes, intestinal K cells or non-endodermal cell types have also been suggested. Stem cells found in bone marrow and umbilical cord blood have been used extensively to repopulate the haematopoietic system and offer the possibility of autologous transplantation. Recent studies have suggested that these stem cells may also have a broader capacity to differentiate, possibly into beta-cells. Stem cells from embryonic sources, such as human embryonic stem and embryonic germ cells, have the ability to proliferate extensively in culture and have an inherent developmental plasticity that may make them a potentially unlimited source of cells that can sense glucose and produce mature insulin. The wide range of proposed cell sources and our increasingly clear picture of pancreatic development suggest that novel cellular therapies might one day compete with non-cellular glucose sensing and insulin delivery devices.