The dual incretin co-agonist tirzepatide increases both insulin secretion and glucose effectiveness in model experiments in mice.

Tirzepatide is a dual GIP and GLP-1 receptor co-agonist which is approved for glucose-lowering therapy in type 2 diabetes. Here, we explored its effects on beta cell function, insulin sensitivity and insulin-independent glucose elimination (glucose effectiveness) in normal mice. Anesthetized female C57/BL/6 J mice were injected intravenously with saline or glucose (0.125, 0.35 or 0.75 g/kg) with or without simultaneous administration of synthetic tirzepatide (3 nmol/kg). Samples were taken at 0, 1, 5, 10, 20 and 50 min. Glucose elimination rate was estimated by the percentage reduction in glucose from min 5 to min 20 (KG). The 50 min areas under the curve (AUC) for insulin and glucose were determined. Beta cell function was assessed as AUCinsulin divided by AUCglucose. Insulin sensitivity (SI) and glucose effectiveness (SG) were determined by minimal model analysis of the insulin and glucose data. Tirzepatide glucose-dependently reduced glucose levels and increased insulin levels. The slope for the regression of AUCinsulin versus AUCglucose was increased 7-fold by tirzepatide from 0.014 ± 0.004 with glucose only to 0.099 ± 0.016 (P < 0.001). SI was not affected by tirzepatide, whereas SG was increased by 78% (P < 0.001). The increase in SG contributed to an increase in KG by 74 ± 4% after glucose alone and by 67 ± 8% after glucose+ tirzepatide, whereas contribution by SI times AUCinsulin insulin (i.e., disposition index) was 26 ± 4% and 33 ± 8%, respectively. In conclusion, tirzepatide stimulates both insulin secretion and glucose effectiveness, with stimulation of glucose effectiveness being the prominent process to reduce glucose.

Anti-diabetic mechanism and potential bioactive peptides of casein hydrolysates in STZ/HFD-induced diabetic rats.

BACKGROUND: Casein hydrolysates have attracted much interest as anti-diabetic food, but their hypoglycemic mechanism and biopeptides are not well understood. This study aimed to explore the anti-diabetic mechanism and potential biopeptides of casein hydrolysates in streptozotocin/high-fat-diet-induced diabetic rats and HepG2 cells. RESULTS: Oral administration of casein hydrolysate prepared with papain-Flavourzyme combination (P-FCH) decreased fasting blood glucose, improved oral glucose tolerance, and reduced HbA1c values in diabetic rats. P-FCH was ineffective in alleviating insulin resistance (homeostasis model assessment and insulin sensitivity index) and enhancing hepatic insulin signaling transduction (phosphorylated Akt, hexokinase activity, and pyruvate kinase activity) in diabetic rats. However, P-FCH significantly upregulated adenosine monophosphate-activated protein kinase phosphorylation and glucose transporter-2 expression, inhibited phosphoenolpyruvate carboxylase kinase activity, and elevated glycogen content in liver tissue of diabetic rats. Furthermore, P-FCH increased glucose consumption independently in normal and insulin-resistant HepG2 cells without the presence of insulin. The peptide composition of P-FCH was characterized. The potential biopeptides in P-FCH showed the sequence characteristic of a Val at the N-terminal or a Pro at the P2 position, and the hypoglycemic activity of Val-Pro-Leu-Gly (the most potential biopeptide in P-FCH) was verified by oral glucose tolerance test in mice. CONCLUSION: These results suggested that activation of the non-insulin-mediated AMPK pathway might be the determinant mechanism of P-FCH on the hypoglycemic effect. The novel peptide Val-Pro-Leu-Gly in P-FCH was effective in reducing blood glucose levels when orally administered to mice. © 2023 Society of Chemical Industry.

Central Nervous System Control of Glucose Homeostasis: A Therapeutic Target for Type 2 Diabetes?

Historically, pancreatic islet beta cells have been viewed as principal regulators of glycemia, with type 2 diabetes (T2D) resulting when insulin secretion fails to compensate for peripheral tissue insulin resistance. However, glycemia is also regulated by insulin-independent mechanisms that are dysregulated in T2D. Based on evidence supporting its role both in adaptive coupling of insulin secretion to changes in insulin sensitivity and in the regulation of insulin-independent glucose disposal, the central nervous system (CNS) has emerged as a fundamental player in glucose homeostasis. Here, we review and expand upon an integrative model wherein the CNS, together with the islet, establishes and maintains the defended level of glycemia. We discuss the implications of this model for understanding both normal glucose homeostasis and T2D pathogenesis and highlight centrally targeted therapeutic approaches with the potential to restore normoglycemia to patients with T2D.

Sodium-Glucose Cotransporter-2 Inhibitors Improve Cardiovascular Dysfunction in Type 2 Diabetic East Asians.

In East Asians, the incidence of type 2 DM (T2DM) has increased as a result of major alterations in life. Cardiovascular problems are more likely in those with T2DM. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are novel insulin-independent antihyperglycemic drugs that limit renal glucose reabsorption and thereby improve glycemic control. They are used alone or in combination with insulin and other antihyperglycemic medications to treat diabetes, and they are also helpful in protecting against the progression of complications. This review has evaluated the available evidence not only on the efficacy of SGLT2 inhibitors in T2DM, but also on their favourable cardiovascular events in East Asians. DM is an independent risk factor for cardiovascular diseases. As a result, in addition to glycemic control in diabetes management, the therapeutic goal in East Asian diabetic patients should be to improve adverse cardiovascular outcomes. Besides establishing antidiabetic effects, several studies have reported cardioprotective benefits of SGLT2 inhibitors via numerous pathways. SGLT2 inhibitors show promising antidiabetic drugs with potential cardiovascular advantages, given that a high number of diabetic patients in East Asia have co-existing cardiovascular disorders. Despite significant positive results in favour of SGLT2, more research is needed to determine how SGLT2 inhibitors exert these impressive cardiovascular effects.

A new approach to treat type 2 diabetes - Targeting a non-insulin dependent pathway.

Diabetes is one of the most urgent healthcare challenges that we are currently facing, and there is a growing need for medications which can manage the condition on a long-term basis. Researchers at Stockholm University working with startup Atrogi AB have developed a novel approach which targets the ß2 adrenergic receptors, circumventing the failing insulin signaling pathway. This unique way of addressing the problem potentially opens the way to a new class of diabetes medications.

Impact of Incretin Hormone Receptors on Insulin-Independent Glucose Disposal in Model Experiments in Mice.

A large contribution to glucose elimination from the circulation is achieved by insulin-independent processes. We have previously shown that the two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) increase this process and, therefore, seem to contribute to glucose disposal both through this effect and through the classical incretin effect resulting in enhanced insulin levels. We have now explored in more detail the potential contribution by incretin hormone receptors to insulin-independent processes for glucose elimination. To that end, we have performed intravenous glucose tests (0.35g/kg) in C57BL/6J mice and analyzed glucose elimination rate and glucose effectiveness (i.e., insulin-independent glucose disposal, SG) in wildtype mice and in mice with genetic deletion of GIP receptors or GLP-1 receptors. We performed studies with or without complete blockade of insulin secretion by the drug diazoxide (25 mg/kg). The mice were anesthetized with a novel fentanyl citrate/fluanisone formulation, called Fluafent, together with midazolam. Initially we demonstrated that glucose and insulin data after intravenous and oral glucose were not different using this anesthesia compared to the previously commonly used combination of HypnormR and midazolam. The results show that SG was reduced in GLP-1 receptor knockout mice, whereas there was no difference between GIP receptor knockout mice and wildtype mice, and this was evident both under normal conditions and after complete inhibition of insulin secretion. The study therefore indicates that insulin-independent glucose elimination requires active GLP-1 receptors and thus that the two incretin hormone receptor types show dissociated relevance for this process.

Insulin Dependence Increases the Risk of 30-Day Postoperative Complications Following Ankle Fracture Surgery in Patients With Diabetes Mellitus.

Patients with diabetes mellitus that undergo ankle fracture surgery have higher rates of postoperative complications compared to patients without diabetes mellitus. We evaluated the rate of complications in insulin-dependent diabetes mellitus patients, non-insulin-dependent diabetes mellitus patients, and patients without diabetes in the 30-day postoperative period following ankle fracture surgery. We also analyzed hospital length of stay, unplanned readmission, unplanned reoperation, and death. Patients who underwent operative management for ankle fractures between 2012 and 2016 were identified in the American College of Surgeons National Surgical Quality Improvement Program® database using Current Procedural Terminology codes. Multiple logistic regression was implemented. Adjusted odds ratios were calculated along with the 95% confidence interval. A total of 19,547 patients undergoing ankle surgery were identified from 2012 to 2016. Of these patients, 989 (5.06%) had insulin-dependent diabetes mellitus, 1256 (6.43%) had noninsulin-dependent diabetes mellitus, and 17,302 (88.51%) did not have diabetes mellitus. Compared to patients without diabetes, patients with insulin-dependent diabetes mellitus had significantly greater adjusted odds of superficial surgical site infections, deep surgical site infections, osteomyelitis, wound dehiscence, pneumonia, unplanned intubation, mechanical ventilation, urinary tract infection, cardiac arrest, bleeding requiring transfusion, sepsis, hospital length of stay, unplanned readmission, unplanned reoperation, and death following ankle fracture surgery. We demonstrate that insulin-dependent diabetes mellitus is a strong predictor of 30-day postoperative complications, unplanned readmission, unplanned reoperation, and death following ankle fracture surgery.

Adaptations in GLUT4 Expression in Response to Exercise Detraining Linked to Downregulation of Insulin-Dependent Pathways in Cardiac but not in Skeletal Muscle Tissue.

Insulin resistance is associated with cardiometabolic risk factors, and exercise training can improve insulin-mediated glucose uptake. However, few studies have demonstrated the reversibility of exercise-induced benefits. Thus, the authors examine the time-response effects of exercise training and detraining on glucose transporter 4 (GLUT4) content, insulin-dependent and insulin-independent pathways in cardiac and gastrocnemius muscle tissues of spontaneously hypertensive rats. Thirty-two male spontaneously hypertensive rats, 4 months old, were assigned to (n = 8/group): T (exercise training: 10-week treadmill exercise, 50-70% maximum effort capacity, 1 hr/day, 5 days/week); D2 (exercise training + 2-day detraining), D4 (exercise training + 4-day detraining); and S (no exercise). The authors evaluated insulin resistance, maximum effort capacity, GLUT4 content, p-IRS-1Tyr1179, p-AS160Ser588, p-AMPKα1Thr172, and p-CaMKIIThr286 in cardiac and gastrocnemius muscle tissues (Western blot). In response to exercise training, there were improvements in insulin resistance (15.4%; p = .010), increased GLUT4 content (microsomal, 29.4%; p = .012; plasma membrane, 27.1%; p < .001), p-IRS-1 (42.2%; p < .001), p-AS160 (60.0%; p < .001) in cardiac tissue, and increased GLUT4 content (microsomal, 29.4%; p = .009; plasma membrane, 55.5%; p < .001), p-IRS-1 (28.1%; p = .018), p-AS160 (76.0%; p < .001), p-AMPK-α1 (37.5%; p = .026), and p-CaMKII (30.0%; p = .040) in the gastrocnemius tissue. In D4 group, the exercise-induced increase in GLUT4 was reversed (plasma membrane, -21.3%; p = .027), p-IRS1 (-37.1%; p = .008), and p-AS160 (-82.6%; p < .001) in the cardiac tissue; p-AS160 expression (-35.7%; p = .034) was reduced in the gastrocnemius. In conclusion, the cardiac tissue is more susceptible to exercise adaptations in the GLUT4 content and signaling pathways than the gastrocnemius muscle. This finding may be explained by particular characteristics of insulin-dependent and insulin-independent pathways in the muscle tissues studied.

Exercise and Insulin Resistance.

In insulin resistance, alterations occur in the signalling pathways that modulate glucose uptake into cells, especially skeletal muscle cells, resulting in impaired glucose homeostasis. Glucose uptake into cells is controlled by a number of pathways, some of which are insulin-dependent. During exercise glucose uptake can occur independently of insulin regulation, and hence research into the effects of exercise on insulin resistance must be clearly defined to reflect whether glucose uptake has been enhanced as a result of the utilisation of these insulin-independent pathways, or whether exercise directly affects insulin resistance in cells. Research into the benefits of exercise for insulin resistance is also problematic in the need to clarify whether it is the exercise itself, or the visceral fat/weight loss that has resulted from the exercise, that has led to improved insulin sensitivity. The research presents a promising picture for the benefits of exercise in insulin resistance.

C-Peptide Area Under the Curve at Glucagon Stimulation Test Predicts Glucose Improvements by GLP-1 Receptor Analogue: A Retrospective Observational Study.

INTRODUCTION: Despite the widespread use of glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1ras) to improve glycemic regulation, with a low risk of hypoglycemia and weight reduction, their effectiveness varies among individuals. This study aimed to identify predictors of the efficacy of GLP-1ra on Hemoglobin A1c (HbA1c) in patients with insulin-independent diabetes. METHODS: In total, 58 patients with insulin-independent diabetes were included. Patients were included if their ß-cell function was evaluated via a glucagon stimulation test (GST) before the introduction of GLP-1ra therapy. ß-Cell function-related indices, such as the C-peptide index (CPI), increments in C-peptide immunoreactivity (CPR) after glucagon stimulation (ΔCPR), and the area under the CPR curve (CPR-AUC) during the GST, were evaluated. HbA1c and body weight (BW) were measured at 6 and 12 months after the initiation of GLP-1ra. RESULTS: A univariate regression analysis revealed a significant correlation between CPR-AUC and changes in HbA1c at 6 months and with changes in BW at 6 and 12 months. A multivariate regression analysis revealed that CPR-AUC was significantly correlated with changes in HbA1c at 6 months. A receiver-operating characteristic analysis revealed that 21.9 ng/ml·min CPR-AUC was the optimal cut-off value to predict an HbA1c level < 7%, i.e., 53 mmol/mol. CONCLUSION: Residual ß-cell function, as assessed via CPR-AUC in the GST, is an effective predictor of the efficacy of GLP-1ras.

Giant umbilical cord and hypoglycemia in an infant with Proteus syndrome.

Proteus syndrome (PS) is characterized by the progressive, segmental, or patchy overgrowth of the skin, and other tissues. This is the first case report of recurrent severe insulin-independent hypoglycemia in an infant with PS. Somatic p.E17K of AKT1 mutation was confirmed. The patient also had a giant umbilical cord, which has not yet been reported in PS.

An Evaluation of the Clinical Therapeutic Effect of Lixisenatide in Type 2 Diabetes Patients: A Systematic Literature Review.

BACKGROUND: With cardiovascular disease accounting for approximately 50% of deaths in patients diagnosed with type 2 diabetes, it is pertinent to initiate anti-diabetic medications with cardiovascular benefits. This systematic clinical review critically examines the clinical therapeutic effect of lixisenatide. METHODS: Data were gathered from articles indexed in PubMed, Google Scholar and Medline from 2010 - 2017, with the following search terms, "lixisenatide" and "GLP-1 receptor agonist". Studies written in the English language were included. RESULTS: Thirteen clinical studies which evaluated the efficacy of lixisenatide were analyzed. Results from these studies showed that lixisenatide is an effective monotherapy in the reduction of glycated hemoglobin (A1C), Postprandial Glucose (PPG) and Fasting Blood Glucose (FPG). As an add-on therapy to metformin or sulfonylureas and insulin, it was found to be clinically effective compared to placebo. In all reviewed trials, there were higher proportions of patients who achieved A1C < 7% or < 6.5% compared to placebo without a corresponding increase in weight. Finally, the use of lixisenatide was not associated with an increased risk of cardiovascular events. The most common adverse events in all lixisenatide groups were nausea, vomiting, and diarrhea. CONCLUSION: Lixisenatide appears to be safe and effective therapy for the management of type 2 diabetes mellitus. It is not associated with either the risk of cardiovascular events or symptomatic hypoglycemia. Finally, lixisenatide may be best used as an adjunct therapy for patients who are inadequately controlled with other diabetic medications, or select group of patients at risk of insulin induced obesity, hypertension or heart failure.

A model of type 2 diabetes in the guinea pig using sequential diet-induced glucose intolerance and streptozotocin treatment.

Type 2 diabetes is a leading cause of morbidity and mortality among noncommunicable diseases, and additional animal models that more closely replicate the pathogenesis of human type 2 diabetes are needed. The goal of this study was to develop a model of type 2 diabetes in guinea pigs, in which diet-induced glucose intolerance precedes ß-cell cytotoxicity, two processes that are crucial to the development of human type 2 diabetes. Guinea pigs developed impaired glucose tolerance after 8 weeks of feeding on a high-fat, high-carbohydrate diet, as determined by oral glucose challenge. Diet-induced glucose intolerance was accompanied by ß-cell hyperplasia, compensatory hyperinsulinemia, and dyslipidemia with hepatocellular steatosis. Streptozotocin (STZ) treatment alone was ineffective at inducing diabetic hyperglycemia in guinea pigs, which failed to develop sustained glucose intolerance or fasting hyperglycemia and returned to euglycemia within 21 days after treatment. However, when high-fat, high-carbohydrate diet-fed guinea pigs were treated with STZ, glucose intolerance and fasting hyperglycemia persisted beyond 21 days post-STZ treatment. Guinea pigs with diet-induced glucose intolerance subsequently treated with STZ demonstrated an insulin-secretory capacity consistent with insulin-independent diabetes. This insulin-independent state was confirmed by response to oral antihyperglycemic drugs, metformin and glipizide, which resolved glucose intolerance and extended survival compared with guinea pigs with uncontrolled diabetes. In this study, we have developed a model of sequential glucose intolerance and ß-cell loss, through high-fat, high-carbohydrate diet and extensive optimization of STZ treatment in the guinea pig, which closely resembles human type 2 diabetes. This model will prove useful in the study of insulin-independent diabetes pathogenesis with or without comorbidities, where the guinea pig serves as a relevant model species.

Amarogentin ameliorates diabetic disorders in animal models.

Amarogentin is a bitter-tasting secoiridoid glycoside isolated from an herb. Inhibition of aldose reductase by amarogentin has been documented as an antidiabetic action. However, the mechanisms of action of amarogentin in diabetic disorders remain unknown. The present study employed streptozotocin-induced type 1 diabetic (T1DM) rats to investigate the antihyperglycemic action of amarogentin. Changes in the protein expression of glucose transporter 4 (GLUT4) and phosphoenolpyruvate carboxykinase (PEPCK) in skeletal muscle and liver, respectively, were also detected by Western blotting. Additionally, a type 2 diabetes (T2DM) animal model induced using a fructose-rich diet was also applied to assess the effect of amarogentin on insulin resistance according to the homeostasis model assessment-insulin resistance (HOMA-IR). Amarogentin dose-dependently attenuated hyperglycemia in the T1DM rats lacking insulin. The action of amarogentin was further supported in rats administered the oral glucose tolerance test. Western blotting showed that amarogentin reversed the decreased GLUT4 level in skeletal muscle and reduced the elevated PEPCK expression in livers isolated from the T1DM rats. Moreover, amarogentin decreased the HOMA-IR and increased insulin sensitivity in the T2DM rats. These data show that amarogentin may ameliorate glucose homeostasis in diabetic rats, indicating its potential for future development as an antidiabetic drug.

Practical considerations for the use of sodium-glucose co-transporter type 2 inhibitors in treating hyperglycemia in type 2 diabetes.

Sodium-glucose co-transporter type 2 (SGLT2) inhibitors are a new class of oral anti-diabetic agents with a unique, insulin-independent mode of action. In patients with diabetes who have adequate renal function, SGLT2 inhibitors reduce hyperglycemia by blocking renal glucose reabsorption and increasing urinary glucose excretion. These agents are indicated for the treatment of hyperglycemia in type 2 diabetes mellitus (T2DM), as an adjunct to diet and exercise. In terms of efficacy, they are comparable to most other oral agents, and carry a low risk of hypoglycemia unless combined with sulfonylureas or insulin. They may be used in combination regimens with metformin, sulfonylureas, or insulin. Beyond glucose lowering, SGLT2 inhibitors are associated with modest weight loss and mild anti-hypertensive effects. Emerging cardiovascular and renal outcomes data suggest other potentially beneficial non-glycemic effects, although these findings await confirmation from further studies. The main adverse effects are increased risk of volume depletion and of genitourinary infections, although these can be managed with standard interventions. Rare cases of euglycemic ketoacidosis have been reported in a subset of patients treated with these agents, an issue currently under investigation. SGLT2 inhibitors represent a promising alternative treatment option for T2DM patients in whom the effectiveness of oral anti-hyperglycemic therapy is limited by the risk of hypoglycemia, weight gain, or other adverse effects. Safety and efficacy (up to 4 years) have been demonstrated in a range of T2DM patient populations, although more studies will be needed to determine whether treatment with SGLT2 inhibitors improves patient-important outcomes in the longer term.

An adenovirus-derived protein: A novel candidate for anti-diabetic drug development.

AIMS: Exposure to human adenovirus Ad36 is causatively and correlatively linked with better glycemic control in animals and humans, respectively. Although the anti-hyperglycemic property of Ad36 may offer some therapeutic potential, it is impractical to use an infectious agent for therapeutic benefit. Cell-based studies identified that Ad36 enhances cellular glucose disposal via its E4orf1 protein. Ability to improve glycemic control in vivo is a critical prerequisite for further investigating the therapeutic potential of E4orf1. Therefore, the aim of this study was to determine the ability of E4orf1 to improve glycemic control independent of insulin despite high fat diet. MATERIALS & METHODS: 8-9wk old male C57BL/6J mice fed a high-fat diet (60% kcal) were injected with a retrovirus plasmid expressing E4orf1, or a null vector (Control). Glycemic control was determined by glucose and insulin tolerance test. Islet cell size, amount of insulin and glucagon were determined in formalin-fixed pancreas. Rat insulinoma cell line (832/13) was infected with E4orf1 or control to determine changes in glucose stimulated insulin secretion. Protein from flash frozen adipose tissue depots, liver and muscle was used to determine molecular signaling by western blotting. RESULTS: In multiple experiments, retrovirus-mediated E4orf1 expression in C57BL/6J mice significantly and reproducibly improved glucose excursion following a glucose load despite a high fat diet (60% energy). Importantly, E4orf1 improved glucose clearance without increasing insulin sensitivity, production or secretion, underscoring its insulin-independent effect. E4orf1 modulated molecular signaling in mice tissue, which included greater protein abundance of adiponectin, p-AKT and Glucose transporter Glu4. CONCLUSIONS: This study provides the proof of concept for translational development of E4orf1 as a potential anti-diabetic agent. High fat intake and impaired insulin signaling are often associated with obesity, diabetes and insulin resistance. Hence, the ability of E4orf1 to improve glycemic control despite high fat diet and independent of insulin, is particularly attractive.

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. In nonobese diabetic (NOD) mice, BAT transplants result in complete reversal of T1D associated with rapid and long-lasting euglycemia. In addition, BAT transplants placed prior to the onset of diabetes on NOD mice can prevent or significantly delay the onset of diabetes. As with streptozotocin (STZ)-diabetic models, euglycemia is independent of insulin and strongly correlates with decrease of inflammation and increase of adipokines. Plasma insulin-like growth factor-I (IGF-I) is the first hormone to increase following BAT transplants. Adipose tissue of transplant recipients consistently express IGF-I compared with little or no expression in controls, and plasma IGF-I levels show a direct negative correlation with glucose, glucagon, and inflammatory cytokines. Adipogenic and anti-inflammatory properties of IGF-I may stimulate regeneration of new healthy white adipose tissue, which in turn secretes hypoglycemic adipokines that substitute for insulin. IGF-I can also directly decrease blood glucose through activating insulin receptor. These data demonstrate the potential for insulin-independent reversal of autoimmune-induced T1D with BAT transplants and implicate IGF-I as a likely mediator in the resulting equilibrium.

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 ß 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. These therapies have their own limitations and complications, some of which can be life-threatening. For example, exogenous insulin administration can lead to fatal hypoglycemic episodes; islet/pancreas transplantation requires life-long immunosuppressive therapy; and anti-diabetic drugs have dangerous side effects including edema, heart failure and lactic acidosis. Thus the need remains for better safer long term treatments for diabetes. The ultimate goal in treating diabetes is to re-establish glucose homeostasis, preferably through endogenously generated hormones. Recent studies increasingly show that extra-pancreatic hormones, particularly those arising from adipose tissue, can compensate for insulin, or entirely replace the function of insulin under appropriate circumstances. Adipose tissue is a versatile endocrine organ that secretes a variety of hormones with far-reaching effects on overall metabolism. While unhealthy adipose tissue can exacerbate diabetes through limiting circulation and secreting of pro-inflammatory cytokines, healthy uninflamed adipose tissue secretes beneficial adipokines with hypoglycemic and anti-inflammatory properties, which can complement and/or compensate for the function of insulin. Administration of specific adipokines is known to alleviate both type 1 and 2 diabetes, and leptin mono-therapy is reported to reverse type 1 diabetes independent of insulin. Although specific adipokines may correct diabetes, administration of individual adipokines still carries risks similar to those of insulin monotherapy. Thus a better approach is to achieve glucose homeostasis with endogenously-generated adipokines through transplantation or regeneration of healthy adipose tissue. Our recent studies on mouse models show that type 1 diabetes can be reversed without insulin through subcutaneous transplantation of embryonic brown adipose tissue, which leads to replenishment of recipients' white adipose tissue; increase of a number of beneficial adipokines; and fast and long-lasting euglycemia. Insulin-independent glucose homeostasis is established through a combination of endogenously generated hormones arising from the transplant and/or newly-replenished white adipose tissue. Transplantation of healthy white adipose tissue is reported to alleviate type 2 diabetes in rodent models on several occasions, and increasing the content of endogenous brown adipose tissue is known to combat obesity and type 2 diabetes in both humans and animal models. While the underlying mechanisms are not fully documented, the beneficial effects of healthy adipose tissue in improving metabolism are increasingly reported, and are worthy of attention as a powerful tool in combating metabolic disease.