Evidence for central regulation of glucose metabolism.

Evidence for central regulation of glucose homeostasis is accumulating from both animal and human studies. Central nutrient and hormone sensing in the hypothalamus appears to coordinate regulation of whole body metabolism. Central signals activate ATP-sensitive potassium (KATP) channels, thereby down-regulating glucose production, likely through vagal efferent signals. Recent human studies are consistent with this hypothesis. The contributions of direct and central inputs to metabolic regulation are likely of comparable magnitude, with somewhat delayed central effects and more rapid peripheral effects. Understanding central regulation of glucose metabolism could promote the development of novel therapeutic approaches for such metabolic conditions as diabetes mellitus.

Diabetes Care in Humanitarian Settings.

Despite the increasing prevalence of diabetes in populations experiencing humanitarian crisis, along with evidence that people living with diabetes are at higher risk for poor outcomes in a crisis, diabetes care is not routinely included in humanitarian health interventions. We here describe 4 factors that have contributed to the inequities and lack of diabetes inclusion in humanitarian programmes: (1) evolving paradigms in humanitarian health care, (2) complexities of diabetes service provision in humanitarian settings, (3) social and cultural challenges, and (4) lack of financing. We also outline opportunities and possible interventions to address these challenges and improve diabetes care among crisis-affected populations.

Using Clinical Vignettes to Understand the Complexity of Diagnosing Type 1 Diabetes in Sub-Saharan Africa.

Lack of awareness, access to insulin and diabetes care can result in high levels of morbidity and mortality for children with type 1 diabetes (T1DM) in sub-Saharan Africa (SSA). Improvements in access to insulin and diabetes management have improved outcomes in some settings. However, many people still present in diabetic ketoacidosis (DKA) in parallel to misdiagnosis of children with T1DM in contexts with high rates of communicable diseases. The aim of this study was to highlight the complexity of diagnosing pediatric T1DM in a healthcare environment dominated by infectious diseases and lack of adequate health system resources. This was done by developing clinical vignettes and recreating the hypothetico-deductive process of a clinician confronted with DKA in the absence of identification of pathognomonic elements of diabetes and with limited diagnostic tools. A non-systematic literature search for T1DM and DKA in SSA was conducted and used to construct clinical vignettes for children presenting in DKA. A broad differential diagnosis of the main conditions present in SSA was made, then used to construct a clinician's medical reasoning, and anticipate the results of different actions on the diagnostic process. An examination of the use of the digital based Integrated Management of Childhood Illness diagnostic algorithm was done, and an analysis of the software's efficiency in adequately diagnosing DKA was assessed. The main obstacles to diagnosis were low specificity of non-pathognomonic DKA symptoms and lack of tools to measure blood or urine glucose. Avenues for improvement include awareness of T1DM symptomatology in communities and health systems, and greater availability of diagnostic tests. Through this work clinical vignettes are shown to be a useful tool in analyzing the obstacles to underdiagnosis of diabetes, a technique that could be used for other pathologies in limited settings, for clinical teaching, research, and advocacy.

Strengthening Diabetes Care in Humanitarian Crises in Low- and Middle-income Settings.

Amid the growing global diabetes epidemic, the scale of forced displacement resulting from armed conflict and humanitarian crises is at record-high levels. More than 80% of the displaced population lives in lower- and middle-income countries, which also host 81% of the global population living with diabetes. Most crises are protracted, often lasting decades, and humanitarian aid organizations are providing long-term primary care to both the local and displaced populations. Humanitarian crises are extremely varied in nature and occur in contexts that are diverse and dynamic. The scope of providing diabetes care varies depending on the phase of the crisis. This paper describes key challenges and possible solutions to improving diabetes care in crisis settings. It focuses on (1) ensuring a reliable supply of life preserving medications and diagnostics, (2) restoring and maintaining access to health care, and (3) adapting service design to the context. These challenges are illustrated through case studies in Ukraine, Mali, the Central African Republic, and Jordan.

An Atypical Form of Diabetes Among Individuals With Low BMI.

OBJECTIVE: Diabetes among individuals with low BMI (<19 kg/m2) has been recognized for >60 years as a prevalent entity in low- and middle-income countries (LMICs) and was formally classified as "malnutrition-related diabetes mellitus" by the World Health Organization (WHO) in 1985. Since the WHO withdrew this category in 1999, our objective was to define the metabolic characteristics of these individuals to establish that this is a distinct form of diabetes. RESEARCH DESIGN AND METHODS: State-of-the-art metabolic studies were used to characterize Indian individuals with "low BMI diabetes" (LD) in whom all known forms of diabetes were excluded by immunogenetic analysis. They were compared with demographically matched groups: a group with type 1 diabetes (T1D), a group with type 2 diabetes (T2D), and a group without diabetes. Insulin secretion was assessed by C-peptide deconvolution. Hepatic and peripheral insulin sensitivity were analyzed with stepped hyperinsulinemic-euglycemic pancreatic clamp studies. Hepatic and myocellular lipid contents were assessed with 1H-nuclear magnetic resonance spectroscopy. RESULTS: The total insulin secretory response was lower in the LD group in comparison with the lean group without diabetes and the T2D group. Endogenous glucose production was significantly lower in the LD group than the T2D group (mean ± SEM 0.50 ± 0.1 vs. 0.84 ± 0.1 mg/kg · min, respectively; P < 0.05). Glucose uptake was significantly higher in the LD group in comparison with the T2D group (10.1 ± 0.7 vs. 4.2 ± 0.5 mg/kg · min; P < 0.001). Visceral adipose tissue and hepatocellular lipids were significantly lower in LD than in T2D. CONCLUSIONS: These studies are the first to demonstrate that LD individuals in LMICs have a unique metabolic profile, suggesting that this is a distinct entity that warrants further investigation.

Insulin-sensitizing effects of vitamin D repletion mediated by adipocyte vitamin D receptor: Studies in humans and mice.

OBJECTIVE: Adipose tissue inflammation and fibrosis appear to contribute to insulin resistance in obesity. Vitamin D receptor (Vdr) genes are expressed by adipocytes, macrophages, and fibroblasts, all of which could potentially play a role in adipose tissue inflammation and fibrosis. As vitamin D has been shown to have direct anti-inflammatory effects on adipocytes, we determined whether specific vitamin D receptor-mediated effects on adipocytes could impact adipose tissue inflammation and fibrosis and ultimately insulin resistance. METHODS: We examined the effects of repleting vitamin D in 25(OH)D-deficient, insulin resistant, overweight-to-obese human subjects (n = 19). A comprehensive assessment of whole-body insulin action was undertaken with stepped euglycemic (∼90 mg/dL) hyperinsulinemic clamp studies both before and after the administration of vitamin D or placebo. Adipose tissue fibrosis and inflammation were quantified by real-time rt-PCR and immunofluorescence in subcutaneous abdominal adipose tissue. To determine whether vitamin D's effects are mediated through adipocytes, we conducted hyperinsulinemic clamp studies (4 mU/kg/min) and adipose tissue analysis using an adipocyte-specific vitamin D receptor knockout (VDR-KO) mouse model (adiponectin-Cre + VDR+/fl) following high-fat diet feeding for 12 weeks. RESULTS: 25(OH)D repletion was associated with reductions in adipose tissue expression of pro-inflammatory and pro-fibrotic genes, decreased collagen immunofluorescence, and improved hepatic insulin sensitivity in humans. Worsening trends after six months on placebo suggest progressive metabolic effects of 25(OH)D deficiency. Ad-VDR-KO mice mirrored the vitamin D-deficient humans, displaying increased adipose tissue fibrosis and inflammation and hepatic insulin resistance. CONCLUSIONS: These complementary human and rodent studies support a beneficial role of vitamin D repletion for improving hepatic insulin resistance and reducing adipose tissue inflammation and fibrosis in targeted individuals, likely via direct effects on adipocytes. These studies have far-reaching implications for understanding the role of adipocytes in mediating adipose tissue inflammation and fibrosis and ultimately impacting insulin sensitivity.

Central KATP Channels Modulate Glucose Effectiveness in Humans and Rodents.

Hyperglycemia is a potent regulator of endogenous glucose production (EGP). Loss of this "glucose effectiveness" is a major contributor to elevated plasma glucose concentrations in type 2 diabetes (T2D). KATP channels in the central nervous system have been shown to regulate EGP in humans and rodents. We examined the contribution of central KATP channels to glucose effectiveness. Under fixed hormonal conditions (studies using a pancreatic clamp), hyperglycemia suppressed EGP by ∼50% in both humans without diabetes and normal Sprague-Dawley rats. By contrast, antagonism of KATP channels with glyburide significantly reduced the EGP-lowering effect of hyperglycemia in both humans and rats. Furthermore, the effects of glyburide on EGP and gluconeogenic enzymes were abolished in rats by intracerebroventricular administration of the KATP channel agonist diazoxide. These findings indicate that about half of the suppression of EGP by hyperglycemia is mediated by central KATP channels. These central mechanisms may offer a novel therapeutic target for improving glycemic control in subjects with T2D.

Inhibiting gluconeogenesis prevents fatty acid-induced increases in endogenous glucose production.

Glucose effectiveness, the ability of glucose per se to suppress endogenous glucose production (EGP), is lost in type 2 diabetes mellitus (T2DM). Free fatty acids (FFA) may contribute to this loss of glucose effectiveness in T2DM by increasing gluconeogenesis (GNG) and impairing the response to hyperglycemia. Thus, we first examined the effects of increasing plasma FFA levels for 3, 6, or 16 h on glucose effectiveness in nondiabetic subjects. Under fixed hormonal conditions, hyperglycemia suppressed EGP by 61% in nondiabetic subjects. Raising FFA levels with Liposyn infusion for > or =3 h reduced the normal suppressive effect of glucose by one-half. Second, we hypothesized that inhibiting GNG would prevent the negative impact of FFA on glucose effectiveness. Raising plasma FFA levels increased gluconeogenesis by approximately 52% during euglycemia and blunted the suppression of EGP by hyperglycemia. Infusion of ethanol rapidly inhibited GNG and doubled the suppression of EGP by hyperglycemia, thereby restoring glucose effectiveness. In conclusion, elevated FFA levels rapidly increased GNG and impaired hepatic glucose effectiveness in nondiabetic subjects. Inhibiting GNG could have therapeutic potential in restoring the regulation of glucose production in type 2 diabetes mellitus.

Challenges associated with providing diabetes care in humanitarian settings.

The humanitarian health landscape is gradually changing, partly as a result of the shift in global epidemiological trends and the rise of non-communicable diseases, including diabetes. Humanitarian actors are progressively incorporating care for diabetes into emergency medical response, but challenges abound. This Series paper discusses contemporary practical challenges associated with diabetes care in humanitarian contexts in low-income and middle-income countries, using the six building blocks of health systems described by WHO (information and research, service delivery, health workforce, medical products and technologies, governance, and financing) as a framework. Challenges include the scarcity of evidence on the management of diabetes and clinical guidelines adapted to humanitarian contexts; unavailability of core indicators for surveillance and monitoring systems; and restricted access to the medicines and diagnostics necessary for adequate clinical care. Policy and system frameworks do not routinely include diabetes and little funding is allocated for diabetes care in humanitarian crises. Humanitarian organisations are increasingly gaining experience delivering diabetes care, and interagency collaboration to coordinate, improve data collection, and analyse available programmes is in progress. However, the needs around all six WHO health system building blocks are immense, and much work needs to be done to improve diabetes care for crisis-affected populations.

The burden of diabetes and use of diabetes care in humanitarian crises in low-income and middle-income countries.

Human suffering as a result of natural disasters or conflict includes death and disability from non-communicable diseases, including diabetes, which have largely been neglected in humanitarian crises. The objectives of this Series paper were to examine the evidence on the burden of diabetes, use of health services, and access to care for people with diabetes among populations affected by humanitarian crises in low-income and middle-income countries, and to identify research gaps for future studies. We reviewed the scientific literature on this topic published between 1992 and 2018. The results emphasise that the burden of diabetes in humanitarian settings is not being captured, clinical guidance is insufficient, and diabetes is not being adequately addressed. Crisis-affected populations with diabetes face enormous constraints accessing care, mainly because of high medical costs. Further research is needed to characterise the epidemiology of diabetes in humanitarian settings and to develop simplified, cost-effective models of care to improve the delivery of diabetes care during humanitarian crises.

Estimation of global insulin use for type 2 diabetes, 2018-30: a microsimulation analysis.

BACKGROUND: The amount of insulin needed to effectively treat type 2 diabetes worldwide is unknown. It also remains unclear how alternative treatment algorithms would affect insulin use and disability-adjusted life-years (DALYs) averted by insulin use, given that current access to insulin (availability and affordability) in many areas is low. The aim of this study was to compare alternative projections for and consequences of insulin use worldwide under varying treatment algorithms and degrees of insulin access. METHODS: We developed a microsimulation of type 2 diabetes burden from 2018 to 2030 across 221 countries using data from the International Diabetes Federation for prevalence projections and from 14 cohort studies representing more than 60% of the global type 2 diabetes population for HbA1c, treatment, and bodyweight data. We estimated the number of people with type 2 diabetes expected to use insulin, international units (IU) required, and DALYs averted per year under alternative treatment algorithms targeting HbA1c from 6·5% to 8%, lower microvascular risk, or higher HbA1c for those aged 75 years and older. FINDINGS: The number of people with type 2 diabetes worldwide was estimated to increase from 405·6 million (95% CI 315·3 million-533·7 million) in 2018 to 510·8 million (395·9 million-674·3 million) in 2030. On this basis, insulin use is estimated to increase from 516·1 million 1000 IU vials (95% CI 409·0 million-658·6 million) per year in 2018 to 633·7 million (500·5 million-806·7 million) per year in 2030. Without improved insulin access, 7·4% (95% CI 5·8-9·4) of people with type 2 diabetes in 2030 would use insulin, increasing to 15·5% (12·0-20·3) if insulin were widely accessible and prescribed to achieve an HbA1c of 7% (53 mmol/mol) or lower. If HbA1c of 7% or lower was universally achieved, insulin would avert 331 101 DALYs per year by 2030 (95% CI 256 601-437 053). DALYs averted would increase by 14·9% with access to newer oral antihyperglycaemic drugs. DALYs averted would increase by 44·2% if an HbA1c of 8% (64 mmol/mol) were used as a target among people aged 75 years and older because of reduced hypoglycaemia. INTERPRETATION: The insulin required to treat type 2 diabetes is expected to increase by more than 20% from 2018 to 2030. More DALYs might be averted if HbA1c targets are higher for older adults. FUNDING: The Leona M and Harry B Helmsley Charitable Trust.

Central Regulation of Glucose Production May Be Impaired in Type 2 Diabetes.

The challenges of achieving optimal glycemic control in type 2 diabetes highlight the need for new therapies. Inappropriately elevated endogenous glucose production (EGP) is the main source of hyperglycemia in type 2 diabetes. Because activation of central ATP-sensitive potassium (KATP) channels suppresses EGP in nondiabetic rodents and humans, this study examined whether type 2 diabetic humans and rodents retain central regulation of EGP. The KATP channel activator diazoxide was administered in a randomized, placebo-controlled crossover design to eight type 2 diabetic subjects and seven age- and BMI-matched healthy control subjects. Comprehensive measures of glucose turnover and insulin sensitivity were performed during euglycemic pancreatic clamp studies following diazoxide and placebo administration. Complementary rodent clamp studies were performed in Zucker Diabetic Fatty rats. In type 2 diabetic subjects, extrapancreatic KATP channel activation with diazoxide under fixed hormonal conditions failed to suppress EGP, whereas matched control subjects demonstrated a 27% reduction in EGP (P = 0.002) with diazoxide. Diazoxide also failed to suppress EGP in diabetic rats. These results suggest that suppression of EGP by central KATP channel activation may be lost in type 2 diabetes. Restoration of central regulation of glucose metabolism could be a promising therapeutic target to reduce hyperglycemia in type 2 diabetes.

Surrogate measures of insulin sensitivity when compared to euglycemic hyperinsulinemic clamp studies in Asian Indian men without diabetes.

AIM: Fasting surrogate measures of insulin sensitivity are increasingly used in research and clinical practice. To assess the reliability of these measures, we aimed to evaluate multiple fasting surrogate measures simultaneously in non-diabetic subjects in comparison with the euglycemic hyperinsulinemic clamp study. METHODS: Sixteen normoglycemic male South Indian subjects were studied. After an overnight fast, blood samples were collected for glucose, insulin and lipid profile measurements, and stepped euglycemic hyperinsulinemic clamp studies were performed on all subjects. Steady state glucose infusion rates (M value) during low and high insulin phases of the clamp were calculated. Correlation of M value with surrogate markers of insulin sensitivity was performed. Predictive accuracy of surrogate indices was measured in terms of Root Mean Squared Error (RMSE) and leave-one-out cross-validation-type RMSE of prediction using a calibration model. RESULTS: M values showed a strong and significant correlation (p<0.01) with the following surrogate markers: Fasting insulin (r=-0.714), Fasting glucose to insulin ratio (FGIR, r=0.747) and Raynaud index (r=0.714). FGIR had a significantly lower RMSE when compared with HOMA-IR and QUICKI. CONCLUSIONS: Among the surrogate measures, FGIR had the strongest correlation with M values. FGIR was also the most accurate surrogate measure, as assessed by the calibration model.

Insulin sensitizing and anti-inflammatory effects of thiazolidinediones are heightened in obese patients.

OBJECTIVE: The American Diabetes Association has called for further research on how patients' demographics should determine drug choices for individuals with type 2 diabetes mellitus (T2DM). Here, using in-depth physiology studies, we investigate whether obese patients with T2DM are likely to benefit from thiazolidinediones, medications with a known adverse effect of weight gain. MATERIALS AND METHODS: Eleven obese and 7 nonobese individuals with T2DM participated in this randomized, placebo-controlled, double-blind, crossover study. Each subject underwent a pair of "stepped" pancreatic clamp studies with subcutaneous adipose tissue biopsies after 21 days of pioglitazone (45 mg) or placebo. RESULTS: Obese subjects demonstrated significant decreases in insulin resistance and many adipose inflammatory parameters with pioglitazone relative to placebo. Specifically, significant improvements in glucose infusion rates, suppression of hepatic glucose production, and whole fat expression of certain inflammatory markers (IL-6, IL-1B, and inducible nitric oxide synthase) were observed in the obese subjects but not in the nonobese subjects. Additionally, adipose tissue from the obese subjects demonstrated reduced infiltration of macrophages, dendritic cells, and neutrophils as well as increased expression of factors associated with fat "browning" (peroxisome proliferator-activated receptor gamma coactivator-1α and uncoupling protein-1). CONCLUSIONS: These findings support the efficacy of pioglitazone to improve insulin resistance and reduce adipose tissue inflammation in obese patients with T2DM.

Reduced adipose tissue macrophage content is associated with improved insulin sensitivity in thiazolidinedione-treated diabetic humans.

Obesity is associated with increased adipose tissue macrophage (ATM) infiltration, and rodent studies suggest that inflammatory factors produced by ATMs contribute to insulin resistance and type 2 diabetes. However, a relationship between ATM content and insulin resistance has not been clearly established in humans. Since thiazolidinediones attenuate adipose tissue inflammation and improve insulin sensitivity, we examined the temporal relationship of the effects of pioglitazone on these two parameters. The effect of 10 and 21 days of pioglitazone treatment on insulin sensitivity in 26 diabetic subjects was assessed by hyperinsulinemic-euglycemic clamp studies. Because chemoattractant factors, cytokines, and immune cells have been implicated in regulating the recruitment of ATMs, we studied their temporal relationship to changes in ATM content. Improved hepatic and peripheral insulin sensitivity was seen after 21 days of pioglitazone. We found early reductions in macrophage chemoattractant factors after only 10 days of pioglitazone, followed by a 69% reduction in ATM content at 21 days and reduced ATM activation at both time points. Although markers for dendritic cells and neutrophils were reduced at both time points, there were no significant changes in regulatory T cells. These results are consistent with an association between adipose macrophage content and systemic insulin resistance in humans.