An orally available compound suppresses glucagon hypersecretion and normalizes hyperglycemia in type 1 diabetes.

Suppression of glucagon hypersecretion can normalize hyperglycemia during type 1 diabetes (T1D). Activating erythropoietin-producing human hepatocellular receptor type-A4 (EphA4) on α cells reduced glucagon hypersecretion from dispersed α cells and T1D islets from both human donor and mouse models. We synthesized a high-affinity small molecule agonist for the EphA4 receptor, WCDD301, which showed robust plasma and liver microsome metabolic stability in both mouse and human preparations.

Brown Adipose Tissue Transplantation.

The metabolic benefits of brown adipose tissue (BAT) are well known. Increasing the BAT content and/or activity is a proposed therapeutic approach to combat metabolic disease. Activation and induction of endogenous BAT have achieved varying degrees of success in correcting obesity, insulin resistance, and cardiovascular disease, with some limitations.

Brown Adipose Expansion and Remission of Glycemic Dysfunction in Obese SM/J Mice.

We leverage the SM/J mouse to understand glycemic control in obesity. High-fat-fed SM/J mice initially develop poor glucose homeostasis relative to controls. Strikingly, their glycemic dysfunction resolves by 30 weeks of age despite persistent obesity.

Insulin-Independent Reversal of Type-1 Diabetes Following Transplantation of Adult Brown Adipose Tissue Supplemented With IGF-1.

Unlabelled: As our previous publications show, it is feasible to reverse type 1 diabetes (T1D) without insulin in multiple mouse models, through transplantation of embryonic brown adipose tissue (BAT) in the subcutaneous space. Embryonic BAT transplants result in rapid and long-lasting euglycemia accompanied by decreased inflammation and regenerated healthy white adipose tissue, with no detectable increase in insulin. To translate this approach to human patients, it is necessary to establish practical alternatives for embryonic tissue.

Adipose tissue NAD biosynthesis is required for regulating adaptive thermogenesis and whole-body energy homeostasis in mice.

Nicotinamide adenine dinucleotide (NAD) is a critical coenzyme for cellular energy metabolism. The aim of the present study was to determine the importance of brown and white adipose tissue (BAT and WAT) NAD metabolism in regulating whole-body thermogenesis and energy metabolism. Accordingly, we generated and analyzed adipocyte-specific nicotinamide phosphoribosyltransferase () knockout (ANKO) and brown adipocyte-specific knockout (BANKO) mice because NAMPT is the rate-limiting NAD biosynthetic enzyme.

Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant.

Traditional therapies for type 1 diabetes (T1D) involve insulin replacement or islet/pancreas transplantation and have numerous limitations. Our previous work demonstrated the ability of embryonic brown adipose tissue (BAT) transplants to establish normoglycemia without insulin in chemically induced models of insulin-deficient diabetes. The current study sought to extend the technique to an autoimmune-mediated T1D model and document the underlying mechanisms.

Benefits of healthy adipose tissue in the treatment of diabetes.

The major malfunction in diabetes mellitus is severe perturbation of glucose homeostasis caused by deficiency of insulin. Insulin deficiency is either absolute due to destruction or failure of pancreatic β cells, or relative due to decreased sensitivity of peripheral tissues to insulin. The primary lesion being related to insulin, treatments for diabetes focus on insulin replacement and/or increasing sensitivity to insulin.

Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch.

A clear relationship exists between visceral obesity and type 2 diabetes, whereas subcutaneous obesity is comparatively benign. Here, we show that adipocyte-specific deletion of the coregulatory protein PRDM16 caused minimal effects on classical brown fat but markedly inhibited beige adipocyte function in subcutaneous fat following cold exposure or β3-agonist treatment. These animals developed obesity on a high-fat diet, with severe insulin resistance and hepatic steatosis.

Therapeutic value of brown adipose tissue: Correcting metabolic disease through generating healthy fat.

Brown adipose tissue (BAT), an important endocrine organ long known for thermogenesis and energy consumption, has received much attention in recent years for its potential to combat obesity. In general, BAT can enhance metabolism and improve overall health. Our recent work demonstrates the ability of embryonic BAT transplants to correct type 1 diabetes (T1D) without insulin, via mechanisms somewhat different from those involved in BAT-associated weight loss.

Adipose tissue, hormones, and treatment of type 1 diabetes.

Type 1 diabetes (T1D) is a serious disease with increasing incidence worldwide, with fatal consequences if untreated. Traditional therapies require direct or indirect insulin replacement, which involves numerous limitations and complications. While insulin is the major regulator of blood glucose, recent reports demonstrate the ability of several extra-pancreatic hormones to decrease blood glucose and improve metabolic homeostasis.

Reversal of type 1 diabetes in mice by brown adipose tissue transplant.

Current therapies for type 1 diabetes (T1D) involve insulin replacement or transplantation of insulin-secreting tissue, both of which suffer from numerous limitations and complications. Here, we show that subcutaneous transplants of embryonic brown adipose tissue (BAT) can correct T1D in streptozotocin-treated mice (both immune competent and immune deficient) with severely impaired glucose tolerance and significant loss of adipose tissue. BAT transplants result in euglycemia, normalized glucose tolerance, reduced tissue inflammation, and reversal of clinical diabetes markers such as polyuria, polydipsia, and polyphagia.

Subcutaneous transplantation of embryonic pancreas for correction of type 1 diabetes.

Islet transplantation is a promising therapeutic approach for type 1 diabetes. However, current success rates are low due to progressive graft failure in the long term and inability to monitor graft development in vivo. Other limitations include the necessity of initial invasive surgery and continued immunosuppressive therapy.

Dimethyl amiloride improves glucose homeostasis in mouse models of type 2 diabetes.

Dimethyl amiloride (DMA) enhances insulin secretion in the pancreatic beta-cell. DMA also enhances time-dependent potentiation (TDP) and enables TDP to occur in situations where it is normally absent. As we have demonstrated before, these effects are mediated in part through inhibition of neuronal nitric oxide synthase (nNOS), resulting in increased availability of arginine.

Direct effect of cholesterol on insulin secretion: a novel mechanism for pancreatic beta-cell dysfunction.

Objective: Type 2 diabetes is often accompanied by abnormal blood lipid and lipoprotein levels, but most studies on the link between hyperlipidemia and diabetes have focused on free fatty acids (FFAs). In this study, we examined the relationship between cholesterol and insulin secretion from pancreatic beta-cells that is independent of the effects of FFAs.

Research Design And Methods: Several methods were used to modulate cholesterol levels in intact islets and cultured beta-cells, including a recently developed mouse model that exhibits elevated cholesterol but normal FFA levels.

Mechanisms of time-dependent potentiation of insulin release: involvement of nitric oxide synthase.

Time-dependent potentiation (TDP) of insulin release is normally absent in mice. However, we recently demonstrated that TDP occurs in mouse islets under conditions of forced decrease of intracellular pH (pH(i)) associated with elevated NADPH+H(+) (NADPH) levels. Hence, TDP in mouse islets may be kept suppressed by neuronal nitric oxide (NO) synthase (nNOS), an NADPH-utilizing enzyme with alkaline pH optimum.

Amiloride derivatives enhance insulin release in pancreatic islets from diabetic mice.

Background: Amiloride derivatives, commonly used for their diuretic and antihypertensive properties, can also cause a sustained but reversible decrease of intracellular pH (pHi). Using dimethyl amiloride (DMA) on normal rodent pancreatic islets, we previously demonstrated the critical influence of islet pHi on insulin secretion. Nutrient-stimulated insulin secretion (NSIS) requires a specific pHi-range, and is dramatically enhanced by forced intracellular acidification with DMA.

Imaging Beta cell development in real-time using pancreatic explants from mice with green fluorescent protein-labeled pancreatic Beta cells.

We present a convenient method for monitoring pancreatic beta cell development in real-time, through in vitro culture of embryonic pancreatic explants from transgenic mice with a genetic tag for insulin-producing beta cells.

Anaplerotic input is sufficient to induce time-dependent potentiation of insulin release in rat pancreatic islets.

Nutrients that induce biphasic insulin release, such as glucose and leucine, provide acetyl-CoA and anaplerotic input in the beta-cell. The first phase of release requires increased ATP production leading to increased intracellular Ca(2+) concentration ([Ca(2+)](i)). The second phase requires increased [Ca(2+)](i) and anaplerosis.

Nutrient-stimulated insulin secretion in mouse islets is critically dependent on intracellular pH.

BACKGROUND: Many mechanistic steps underlying nutrient-stimulated insulin secretion (NSIS) are poorly understood. The influence of intracellular pH (pHi) on insulin secretion is widely documented, and can be used as an investigative tool. This study demonstrates previously unknown effects of pHi-alteration on insulin secretion in mouse islets, which may be utilized to correct defects in insulin secretion.

Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion.

The insulin secretory response by pancreatic beta-cells to an acute "square wave" stimulation by glucose is characterized by a first phase that occurs promptly after exposure to glucose, followed by a decrease to a nadir, and a prolonged second phase. The first phase of release is due to the ATP-sensitive K(+) (K(ATP)) channel-dependent (triggering) pathway that increases [Ca(2+)](i) and has been thought to discharge the granules from a "readily releasable pool." It follows that the second phase entails the preparation of granules for release, perhaps including translocation and priming for fusion competency before exocytosis.

Intracellular pH plays a critical role in glucose-induced time-dependent potentiation of insulin release in rat islets.

The underlying mechanisms of glucose-induced time-dependent potentiation in the pancreatic beta-cell are unknown. It had been widely accepted that extracellular Ca(2+) is essential for this process. However, we consistently observed glucose-induced priming under stringent Ca(2+)-free conditions, provided that the experiment was conducted in a HEPES-buffered medium as opposed to the bicarbonate (HCO(3)(-))-buffered medium used in previous studies.