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Despite ongoing advances in medications, insulin delivery systems, and glucose monitoring technologies, diabetes control remains suboptimal in many individuals with this disease.1 In addition to the clinical consequences resulting from poor control is the ever-increasing financial burden on individuals, health systems, and society.2 In its latest report, the American Diabetes Association (ADA) estimated the total estimated cost of diagnosed diabetes in 2017 to be $327 billion.2 Although the direct cost of treating complications (hospitalizations, emergency room visits, and nondiabetes prescription medications) and the indirect costs associated with lost/reduced productivity account for ∼73.1% of the total diabetes cost, many public and private payers continue to focus much of their cost-cutting efforts on reducing the costs of diabetes supplies, which account for only 1.1% of the total cost. Examples of these questionable efforts can be found in the restrictive eligibility criteria for coverage of continuous glucose monitoring (CGM). Specifically, the requirements are that eligible individuals must have type 1 diabetes (T1D) and be able to document routine performance of at least four fingerstick blood glucose tests per day. The Centers for Medicare and Medicaid Services (CMS) explicitly requires this level of testing for Medicare beneficiaries to qualify for CGM coverage, as do 11 of 36 state Medicaid programs that provide CGM coverage. Requiring documentation of >4 blood glucose tests per day is clearly enigmatic given that the Medicare coverage policy only pays for three test strips per day for insulin-treated beneficiaries. Although Medicare coverage includes both T1D and intensively treated type 2 diabetes (T2D), many state Medicaid programs do not match such coverage. A comprehensive Internet search found that 13 state programs limit CGM use to individuals with T1D and documented history of 4 × /day blood glucose testing (Table 1). Three programs cover both T1D and insulin-requiring T2D but with the minimum blood glucose monitoring restriction. Four programs cover T1D with no blood glucose monitoring restriction, and only one state covers both type 1 and insulin-requiring diabetes with no blood glucose restriction. Eligibility for CGM in the remaining 14 State Medicaid programs is not specified or accessible according to our Internet search. Table 1. Medicaid Coverage for Continuous Glucose Monitoring Use

Numerous randomized controlled trials (RCTs) have demonstrated the glycemic benefits of continuous glucose monitoring (CGM) in management of type 1 diabetes (T1D) and type 2 diabetes. Although RCTs remain the gold standard clinical study design, findings from these trials do not necessarily reflect the effectiveness of CGM or reveal the feasibility and wider applications for use in broader real-life settings. This review evaluates recent real-world evidence (RWE) demonstrating the value of CGM to improve clinical outcomes, such as avoidance of severe hypoglycemic and hyperglycemic crises, and improved measures of psychological health and quality of life. Additionally, this review considers recent RWE for the role of CGM to enhance health care resource utilization, including prediction of T1D and applications in gestational diabetes, chronic kidney disease, and monitoring during surgery.

Optimizing glycemic control remains a shared challenge for clinicians and their patients with diabetes. Flash continuous glucose monitoring (CGM) provides immediate information about an individual’s current and projected glucose level, allowing users to respond promptly to mitigate or prevent pending hypoglycemia or hyperglycemia. Large randomized controlled trials (RCTs) have demonstrated the glycemic benefits of flash CGM use in both type 1 and type 2 diabetes. However, whereas RCTs are mostly focused on the efficacy of this technology in defined circumstances, real-world studies can assess its effectiveness in wider clinical settings. This review assesses the most recent real-world studies demonstrating the effectiveness of flash CGM use to improve clinical outcomes and health care resource utilization in populations with diabetes.

The use of personal continuous glucose monitoring (CGM) has expanded dramatically among individuals with diabetes. CGM systems provide retrospective data, as well as the current glucose value and trend arrow data, which indicate the direction and velocity of changing glucose. In 2017, Aleppo and colleagues developed a simplified approach for adults with diabetes to safely adjust rapid-acting insulin doses using trend arrow information in the Dexcom G5 CGM system. Since then, the FreeStyle Libre and FreeStyle Libre 14-day CGM systems have become available in the United States; however, guidance on using trend arrow data that take the unique features of these systems into consideration is lacking. Specifically, the FreeStyle Libre systems do not have automatic alarms, which impact how the system and trend arrow data are used. The Endocrine Society convened an expert panel to address this gap and develop an approach to adjusting rapid-acting insulin doses for adults using trend arrows in the FreeStyle Libre systems. We based our approach on previous work and expanded upon engagement and scanning recommendations, and we incorporated pre-exercise planning specific to these systems. Our approach provides insulin dose adjustments as discrete insulin units based on an individual’s insulin sensitivity and directionality of the trend arrow. We focus on the needs of patients treated with multiple daily injections because these individuals currently make up a greater proportion of individuals on intensive insulin therapy. Our recommendations are intended to provide a safe, practical approach to using trend arrows in the FreeStyle Libre systems.

Diabetes is epidemic worldwide and places a huge burden on healthcare systems. The majority of the cost of type 2 diabetes (T2D) is related to hospitalization and the management of complications, and these also have a negative impact on the individual’s quality of life. The Berlin Declaration is a global call for early action for the identification of high risk individuals, prevention of T2D and the prevention of complications in those with T2D, through prevention, early detection, early control and early access to the right multidisciplinary interventions. This should empower people to take action to prevent T2D and its complications.

Diabetes is a major global epidemic and places a huge burden on healthcare systems worldwide. The complications of type 2 diabetes (T2D) and related hospitalizations are major contributors to this burden, and there is strong evidence that the risk for these can be reduced by early action to identify and prevent progression of people at high risk of T2D and ensure tight glycemic control in those with established disease. In response to this, the Berlin Declaration was developed by four working groups of experts and ratified by healthcare professionals from 38 countries. Its aim is to act as a global call to action for early intervention in diabetes, in addition to providing short-, medium- and long-term targets that should be relevant to all nations. The Berlin Declaration focuses on four aspects of early action, and proposes actionable policies relating to each aspect: early detection, prevention, early control and early access to the right interventions. In addition, a number of treatment targets are proposed to provide goals for these policies. To ensure that the suggested policies are enacted in the most effective manner, the support of specialist care professionals is considered essential.

Advances in understanding diabetes mellitus (DM) through basic and clinical research have helped clarify and reunify a disease state fragmented into numerous etiologies and subtypes. It is now understood that a common pathophysiology drives the diabetic state throughout its natural history and across its varied clinical presentations, a pathophysiology involving metabolic insults, oxidative damage, and vicious cycles that aggravate and intensify organ dysfunction and damage. This new understanding of the disease requires that we revisit existing diagnostics and treatment approaches, which were built upon outmoded assumptions. 'The Common Pathophysiologic Origins of Diabetes Mellitus and its Complications Construct' is presented as a more accurate, foundational, and translatable construct of DM that helps make sense of the hitherto ambiguous findings of long-term outcome studies.

The current classification system presents challenges to the diagnosis and treatment of patients with diabetes mellitus (DM), in part due to its conflicting and confounding definitions of type 1 DM, type 2 DM, and latent autoimmune diabetes of adults (LADA). The current schema also lacks a foundation that readily incorporates advances in our understanding of the disease and its treatment. For appropriate and coherent therapy, we propose an alternate classification system. The β-cell–centric classification of DM is a new approach that obviates the inherent and unintended confusions of the current system. The β-cell–centric model presupposes that all DM originates from a final common denominator—the abnormal pancreatic β-cell. It recognizes that interactions between genetically predisposed β-cells with a number of factors, including insulin resistance (IR), susceptibility to environmental influences, and immune dysregulation/inflammation, lead to the range of hyperglycemic phenotypes within the spectrum of DM. Individually or in concert, and often self-perpetuating, these factors contribute to β-cell stress, dysfunction, or loss through at least 11 distinct pathways. Available, yet underutilized, treatments provide rational choices for personalized therapies that target the individual mediating pathways of hyperglycemia at work in any given patient, without the risk of drug-related hypoglycemia or weight gain or imposing further burden on the β-cells. This article issues an urgent call for the review of the current DM classification system toward the consensus on a new, more useful system.

We thank Drs. Kalra and and Baruah for their comments (1) on our article (2) in an effort improve the utility of our proposed β-cell–centric classification. We agree that “treatment” is more important than “classification.” We find it frustrating that governments and insurers often think otherwise, limiting therapies of choice on the basis of labels of diabetes mellitus (DM) that are not optimally useful. Thus a “precision medicine” classification system that identifies specific causes of hyperglycemia and their corresponding therapies augurs for payment coverage parity across the range of glucose-lowering medications for patients with any form of DM. Although the insulin-to-glucagon ratio (IGR) construct is interesting and could serve as a “marker” to help choose between various therapies in our approach, our …

Purpose Current evidence shows early initiation of insulin therapy in type 2 diabetes mellitus (T2DM) improves glycemic control, responsiveness to subsequent oral antidiabetic therapies, β-cell function, and possible cardiovascular outcomes. The American Diabetes Association (ADA)/ European Association for the Study of Diabetes (EASD) 2008 algorithm introduces insulin therapy earlier in the treatment of T2DM with prompt intensification to achieve therapeutic goals. Agent selection and insulin regimens are based on patient A1C levels and willingness to monitor blood glucose, use of previous medications, blood glucose patterns, diet, and lifestyle. Practical considerations offered for diabetes educators and clinicians include creating strategies for early initiation of insulin, addressing patients’ psychosocial barriers and quality of life concerns, understanding pharmacokinetic properties of insulin formulations, selecting appropriate therapy and patient-based regimens, and intensifying therapy to achieve glycemic control. Conclusions Diabetes education, including intentional curriculum design, for patients with T2DM who are initiating or intensifying insulin therapy, addresses patient barriers to care, reduces the burden of treatment, improves adherence to treatment protocols, and helps optimize clinical outcomes.

Objective To discuss the appropriate use of oral therapies to achieve and sustain glycemic targets in patients with type 2 diabetes. Methods The stages in the development and progression of type 2 diabetes are reviewed, and the limitations of single-drug therapy are addressed. Results The development of diabetes is a staged progression; affected patients show evolution through numerous stages of glucose intolerance before clinical diabetes manifests. Beta cell function continues to deteriorate until absolute failure occurs; however, other factors, such as glucose and lipid toxicities, insulin resistance in peripheral tissues, and loss of the first-phase insulin response, further impair the body’s ability to regulate release of insulin in response to glucose. Traditional treatment algorithms often fail to address the progressive, multifaceted nature of type 2 diabetes, with its numerous related abnormalities. Combination therapy with orally administered agents can be used to manage glucose concentrations and other risk factors safely and effectively. Conclusion The therapeutic goal in type 2 diabetes is to achieve and maintain a physiologic profile as close to normal as possible. This outcome necessitates treatment of multiple defects with use of various combinations of orally administered agents. Clinicians should focus on effective treatment of these defects to achieve established targets. (Endocr Pract. 2006;12[Suppl 1]:93-97)

The prevalence of type 2 diabetes has grown to epidemic proportions in the United States and is disproportionately higher in certain ethnic groups. African Americans, Hispanic Americans, Native Americans, and Asian Americans have an approximately two‐fold higher rate of type 2 diabetes than whites. The increased prevalence of type 2 diabetes mirrors the growing rates of overweight and obese persons in the United States. While the highest rate of diabetes occurs at age 60 years and older, the fastest growing segment of the population with type 2 diabetes is younger than age 39 years. Because most diabetes‐related deaths are due to cardiovascular disease, an aggressive management strategy for type 2 diabetes must address both coronary heart disease risk factor reduction and glycemic control. Both the microvascular and macrovascular complications of type 2 diabetes can be prevented or slowed with aggressive therapy. Glycemic dysfunction can be moderated by aggressive combination therapy that focuses on the pathophysiology of diabetes in an individual patient and combines two or three oral agents, such as an insulin sensitizer with an insulin secretagogue or two insulin sensitizers with different loci of action. The goal of glycemic control is reduction of glycated hemoglobin to 40 mg/dL for men and >50 mg/dL for women, and decrease triglyceride levels to

There is overwhelming evidence that the renin-angiotensin system plays a significant role in the pathophysiology of hypertension and target organ damage. Agents that regulate the renin-angiotensin system, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, and aldosterone antagonists, are not only effective antihypertensive agents but can prevent target organ damage. Although diuretics remain the agents of first choice for the treatment of hypertension in African Americans, ACE inhibitors have a clear role in the management of these patients. ACE inhibitors (usually when used with a diuretic) have been shown to reduce morbidity and mortality in a wide range of patient groups. ACE inhibitors are infrequently used in African Americans because of a belief that these agents are ineffective in this racial group; however, when adequate dosing and appropriate combinations are used, ACE inhibitor therapy provides effective blood pressure control. In particular, the addition of diuretics to ACE inhibitor therapy ameliorates the racial differences in efficacy seen when ACE inhibitors are administered as monotherapy. Although further confirmation in additional clinical trials is required, increased use of these agents in African Americans will likely result in a reduction in target organ damage.

T he U.S. Department of Health and Human Services' National Diabetes Education Program (NDEP) is the leading federal government public education program that promotes diabetes prevention and control. Based on the scientific results of the Diabetes Control and Complications Trial,1 NDEP was launched in 1997 with a mission to reduce the morbidity and mortality associated with diabetes. To fulfill that mission, NDEP translates the latest science and disseminates the message that type 2 diabetes is serious, common, and costly, yet controllable and preventable. NDEP is jointly sponsored by the National Institutes of Health and the Centers for Disease Control and Prevention, with the support of > 200 partner organizations. Health care professionals need to know about current advances in diabetes management and prevention and require access to the most appropriate and effective tools and materials to assist them in administering the most effective care. NDEP provides a wealth of information and tools through three major campaigns: 1. Control Your Diabetes. For Life. This is a comprehensive information campaign focusing on tips and strategies for effective diabetes management. 2. Be Smart About Your Heart: Control the ABCs of Diabetes. This emphasizes the link between diabetes and cardiovascular disease. 3. Small Steps. Big Rewards. Prevent Type 2 Diabetes. This is the first national diabetes prevention effort. In view of the spiraling epidemic of diabetes in …

Type 2 diabetes has been definitively characterized as one of the most physiologically complex and heterogeneous metabolic known diseases. The extraordinary depth of knowledge that has been achieved regarding the pathophysiology has helped to stimulate an explosive array of therapeutic regimens and monitoring tools for improving outcomes in this disease. Indeed, the clinical narrative about ‘control’ of diabetes has shifted markedly in the last two years, away from a focus on glucose-mediated vascular complications to defining diabetes control as cardiovascular risk reduction and end organ protection. The new tools for management coupled with new pathophysiologic insights have brought a tide of good news for the millions of people living with type 2 diabetes.

Alan J. Garber, MD, PhD, FACE, Yehuda Handelsman, MD, FACP, FACE, Daniel Einhorn, MD, FACP, FACE, Donald A. Bergman, MD, FACE, Zachary T. Bloomgarden, MD, FACE, Vivian Fonseca, MD, FACE, W. Timothy Garvey, MD, James R. Gavin III, MD, PhD, George Grunberger, MD, FACP, FACE, Edward S. Horton, MD, FACE, Paul S. Jellinger, MD, MACE, Kenneth L. Jones, MD, Harold Lebovitz, MD, FACE, Philip Levy, MD, MACE, Darren K. McGuire, MD, MHSc, FACC, Etie S. Moghissi, MD, FACP, FACE, and Richard W. Nesto, MD, FACC, FAHA

Current clinical guidelines for diabetes care encourage self-monitoring of blood glucose (SMBG) to improve glycemic control. Specific protocols remain variable, however, particularly among non-insulin-using patients. This is due in part to efficacy studies that neglect to consider (1) the performance of monitoring equipment under real-world conditions, (2) whether or how patients have been taught to take action on test results, and (3) the physiological, behavioral, and social circumstances in which SMBG is carried out. As such, a multidisciplinary group of specialists, including several endocrinologists, a health psychologist, a diabetes nurse practitioner, and a patient advocate (the Panel), discuss within this review article how the potential of SMBG might be fully realized in today's healthcare environment. The resulting recommendations cover technological, clinical, behavioral, and research considerations with the aim of achieving short- and long-term benefits, ranging from fewer hypoglycemic episodes to lower complication-related costs. The panel also made suggestions for designing future studies that increase the ability to discern optimal models of SMBG utilization for individuals with diabetes who may, or may not, use insulin.

Because skeletal muscle plays a major role in glucose disposal, it may be the primary site of insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM). Rates of glycogen synthesis (GS), glucose utilization via glycolysis, glycolytic utilization (GU), and glucose transport (GT) were studied in epitrochlearis muscles (EMs) obtained from 10-wk-old nonfasted Sprague-Dawley rats in which NIDDM was neonatally induced with streptozocin. Plasma glucose in NIDDM rats was elevated (P < 0.001), whereas plasma insulin was similar in NIDDM and control rats. No differences in muscle weight, protein, glycogen, ATP, phosphocreatine, lactate, lactate-pyruvate ratios, or glucose-6-phosphate were noted in EMs of control and NIDDM rats. EMs were incubated in medium containing 5.6 or 11.2 mM glucose with tracer D-[5-3H]glucose and insulin from 0 to 7.18 × 10−7 M for 1 or 2 h, and GS, GT, and GU were evaluated. Similar rates of basal (non-insulin-mediated) and insulin-stimulated GS, GU, and GT were observed in EMs of NIDDM and control rats incubated in 5.6 mM glucose for 2 h. Insulin doseresponse curves revealed similar sensitivities and responsiveness. Increasing glucose concentration (from 5.6 to 11.2 mM) induced significant increases in basal rates of GS, GU, and GT in EMs of control but not NIDDM rats. Insulin dose-response curves for GS and GT revealed decreased sensitivity and no change in responsiveness in EMs of control and NIDDM rats, even though GU of EMs of NIDDM rats was significantly lower at basal and all other insulin concentrations. These data revealed that both insulin resistance and glucose resistance contribute to the impaired glucose metabolism in EMs of the NIDDM rat.

Insulin increases (Ca2+ + Mg2+)-ATPase activity in cell membranes of normal rats but fails to do so in membranes of non-insulin-dependent diabetic (NIDD) rats. The loss of regulatory effect of the hormone on the enzyme might contribute to the insulin resistance observed in the NIDD animals. To further test this hypothesis, the effects of insulin treatment and acute food restriction on the ability of insulin to regulate the ATPase activity in kidney basolateral membranes (BLM) of NIDD rats were studied. Although insulin levels in NIDD and control rats were similar, plasma glucose was higher in the NIDD rats (18.3 ± 1.5 v 19.3 ± 1.7 μU/mL and 236 ± 32 v 145 ± 3 mg/dL, respectively). Insulin treatment (2 U100 g), which increased plasma insulin in the NIDD rats (47.8 ± 11.5 μU/mL; P < .05), did not decrease their glucose (221 ± 25 mg/dL). Higher insulin dose (4 U100 g) decreased glucose level in the NIDD rats (73 ± 3 mg/dL; P < .001) but increased their plasma insulin 10-fold (202.5 ± 52.5 μU/mL). Acute food restriction decreased glucose levels in the NIDD rats to levels seen in controls (135 ± 3 mg/dL), while their insulin decreased by half (8.5 ± 1.0 μU/mL; P < .05). Basal (Ca2+ + Mg2+)-ATPase activity in BLM of all diabetic rats was higher than in controls (P < .05). None of the treatments reversed this defect. Insulin (12.5 to 200 μU/mL) increased the ATPase activity (10% to 40%) in BLM from controls but not from NIDD rats. In BLM from food-restricted diabetic rats, insulin increased the enzyme activity by 16% to 42%, but the dose-response curve was shifted to the right. In BLM from insulin-treated rats, insulin caused a slight (10% to 20%) increase in enzyme activity only at its highest concentration (200 μU/mL). These findings confirm the existence of insulin resistance in the NIDD rats and reveal that acute food restriction ameliorates it. The amelioration of insulin resistance was accompanied by a regained ability of insulin to regulate the membrane (Ca2+ + Mg2+)-ATPase. It is suggested that part of the beneficial effect of food restriction on insulin resistance in the NIDD rat is due to a restoration of insulin's ability to regulate cell Ca2+ homeostasis.

Long-term pharmacologic strategies that may be used in conjunction with lifestyle changes to combat the obesity epidemic have, until recently, been an unmet clinical need. In 2012, the US Food and Drug Administration (FDA) approved two new drugs for chronic weight management in obese adults in conjunction with a reduced-calorie diet and increased physical activity: phentermine/topiramate extended-release (PHEN/TPM ER) and lorcaserin. The efficacy and safety of PHEN/TPM ER has been studied in clinical trials. PHEN/TPM ER had a substantial impact on weight loss with the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) target of 10 % weight loss from baseline being achieved in almost half of patients receiving PHEN/TPM ER 15/92. Furthermore, PHEN/TPM ER was associated with improvement in obesityrelated adverse health consequences, including hyperglycemia, dyslipidemia, and hypertension, and a reduction in the rate of progression to type 2 diabetes. This clinical evidence supports PHEN/TPM ER as an efficacious, well-tolerated anti-obesity agent that may also have a significant impact on obesity-related adverse health consequences.

SUPP. 1 VOL. VI NO. IV APRIL 2004 2 There is an increasing international epidemic of cardiovascular disease (CVD). Of all deaths worldwide, 30% are attributed to CVD. A primary reason for this global burden is the failure to slow the emergence of CVD risk factors such as obesity, diabetes, and/or chronic kidney disease. In the United States, cardiovascular events remain a major burden on society, and of all segments of the population, African Americans have the highest death rate from CVD. With this perspective, a roundtable meeting including more than a dozen experts from a variety of backgrounds was assembled April 24–25, 2003, to review the evidence-based science supporting best practices for the management of CVD and its complications in African-American patients. This supplement to The Journal of Clinical Hypertension is a result of that meeting. Dr. Kenneth Jamerson begins by describing in detail the increasing incidence of CVD in African Americans. He provides data highlighting the major increase in the incidence of all forms of CVD in African Americans compared with white Americans and provides a needed perspective to assist health care providers in understanding the extremely high level of CVD in African Americans. Dr. Gary Gibbons’s article focuses on genetics and physiology. He shares the latest and most important research directed at the unique characteristics of African Americans with CVD. Dr. Gibbons explores the genetic and physiologic differences that may explain why African Americans are more susceptible to sodium retention, left ventricular hypertrophy, and vascular injury. Reported polymorphisms of the β-1 receptor, renin-angiotensin-aldosterone system, and endothelial nitric oxide synthase are explained and their relevance is described. The article also explores why African Americans appear to derive less benefit from certain drug classes. In the next article, Dr. Elijah Saunders discusses managing hypertension in this high-risk group. Blood pressure control is critical in African Americans with hypertension, who are at very high risk for cardiovascular and cardiorenal events. Dr. Saunders reviews recent clinical trial data and constructs a treatment algorithm for controlling BP in this patient population. He explores the pros and cons of the spectrum of available pharmacologic agents and applies these data to the treatment of hypertension in the African-American population. Finally, Dr. Saunders explains the need for and benefits of combination antihypertensive therapy. Dr. James Gavin not only addresses the issue of African-American patients with diabetes; but also all Americans with type 2 diabetes. There are now nearly 17 million persons with diabetes in the United States (>6% of the general population) and 95% are classified as having type 2 disease. There has been a doubling of the prevalence over the past decade, and this is clearly coupled with the advancing epidemic of obesity and the sedentary lifestyle www.lejacq.com ID: 3559 I n t r o d u c t i o n

Purpose To review epidemiologic data for prevalence of diabetes in high-risk minority populations in the United States, drawing on recently published epidemiologic studies to summarize the effect of a worldwide diabetes epidemic in high-risk populations. Findings The epidemic of diabetes in the United States is heavily influenced by the degree of penetration of the disease in populations of ethnic Americans. Although the largest percentage increase in diabetes during the past decade was in the 30- to 39-year-old age-group, high-risk minorities such as African Americans, Hispanic Americans, and American Indians have also had an increased prevalence of type 2 diabetes in children and adolescents. At the other end of the age spectrum, type 2 diabetes is increasing among the aging “baby boomers.” Both an increased risk of developing diabetes and an increased occurrence of diabetes-related complications, such as retinopathy and end-stage renal disease, are evident in ethnic minorities in comparison with whites. The possible reasons for this increased risk include (1) differences in lifestyle preferences and choices, (2) more limited access to health care, (3) poorer quality of health care, and (4) biologic or genetic determinants. Conclusion Additional research is needed to determine whether these differences predict a varied clinical course for diabetes in high-risk populations and whether they compel a different approach to treatment.

In people with normal glucose tolerance, blood glucose levels are automatically monitored and controlled by the body. After eating, the body releases enough insulin to keep the plasma glucose within a normal range that rarely rises above 7.8mmol/l (140mg/dl) and usually returns to pre-meal levels within two to three hours. In people with impaired glucose tolerance or diabetes, the body has little or no automatic control of blood glucose levels. After eating, they often experience extended periods of elevated blood glucose levels.

In most patients with acromegaly basal serum GH concentrations are elevated and remain above 5 micrograms/L after oral glucose administration. In some patients, however, serum insulin-like growth factor I (IGF-I) concentrations are elevated with only minimal elevations of serum GH. We studied the serum GH and IGF-I of two such patients to determine whether these peptide hormones are normal in this clinical situation. The serum GH of these patients was found to bind normally to receptors of the IM-9 lymphocyte. The elution pattern of IGF-I extracted from the patients' serum was similar to that of (Thr59) human IGF-I after passage through a Bio-Rad P-60 column in 0.5 M acetic acid. The IGF-I was further characterized by isoelectric focusing and C18 reverse phase high pressure liquid chromatography (HPLC). The isoelectric points of the IGF-I components were similar to those of IGF-I in normal serum. The IGF-I in one patient had two components by HPLC, while that of the other patient had only one major component. The IGF-I components isolated by HPLC were normally active in stimulating [3H] alpha-aminoisobutyric acid uptake by normal human fibroblasts. The elevated serum IGF-I concentrations of these two patients were GH dependent. Transsphenoidal adenomectomy in one patient resulted in a decline in serum IGF-I to a high normal concentration. Lowering the serum GH to subnormal concentrations by the administration of the somatostatin analog SMS 201-995 (Sandoz) restored normal IGF-I concentrations in the second patient. We conclude that the GH and IGF-I of these two patients cannot account for their apparent enhanced GH responsiveness.

The activity of (Ca2+ +Mg2+)-ATPase is impaired in kidney basolateral membranes from non-insulin-dependent streptozotocin-diabetic rats. To study the possible role of changes in membrane phospholipid content in the malfunction of this enzyme in kidney membranes of the diabetic animals, phospholipid (phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, and sphingomyelin) content was measured in kidney and liver membranes obtained from non-insulin-dependent diabetic rats. Total phospholipid content was similar in liver and kidney membranes of diabetic and control rats (595 +/- 47 versus 624 +/- 29 in liver and 469 +/- 22 versus 458 +/- 17 nmol Pi/mg protein in kidney respectively). Phosphatidylethanolamine content in kidney and liver membranes of diabetic rats was lower than in control rats (87.7 +/- 1.8 versus 96.4 +/- 2.2 nmol Pi/mg protein, p less than 0.01 and 87.1 +/- 3.7 versus 101.8 +/- 3.5, p less than 0.02 respectively). Phosphatidylinositol content was higher in kidney (28.0 +/- 0.6 versus 23.9 +/- 2.1, p less than 0.02) but not liver membranes from diabetic rats. The in vitro direct effect of insulin on the phospholipid content in kidney membranes was also measured. Physiologic concentrations of insulin (718 pmol/l for 30 min) increased the phosphatidic acid content in membranes from control but not from diabetic rats by 34.2% (p less than 0.02). This rise was readily measurable after 3 min of exposure to insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of mild, non-insulin-dependent diabetes (NIDDM) on bone calcification and calcium (Ca) homeostasis was studied in growing rats (males and females). The diabetic state was characterized by mild insulin deficiency, plasma levels being 73% of controls, and mild hyperglycemia, with nonfasting plasma glucose levels of 1.5 times normal. There was no difference in plasma levels of Ca, phosphate (Pi), magnesium (Mg), alkaline phosphatase, immunoreactive parathyroid hormone (iPTH), calcitonin, 25-(OH)vitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25[OHrsqb;2D), and 24,25-dihydroxyvitamin D (24,25[OH]2D) between the NIDDM rats and their controls of either sex. Metabolic Ca and Pi balance studies revealed that the experimental animals of both sexes were in positive Ca and Pi balance similar to that of their controls. Histologic studies of the kidney and intestinal slices from the experimental group were normal. Ca and Pi bone content calculated per gram bone ash of the femur, mandible, and second and fourth caudal vertebrae, and the organic content in the bones of the NIDDM animals showed no difference from their controls. Femur bone density and tibial epiphyseal growth plate width and morphology were similar histologically in the experimental and control rats. No decreased osteoid content in the tibial bone was found in the diabetic rats compared with controls. Physiologic sex differences, consisting of lower plasma Pi, higher plasma calcitonin levels, increased ratio of femur dry bone weight to total body weight, and increased percentage of mineralized and total bone volume at the tibial metaphysis seen in female compared with male control rats were also seen in the diabetic animals. The data reveal that, in states of mild insulin deficiency in the rat, the factors that regulate mineral metabolism are functioning normally and bone mineralization proceeds without alterations. In addition, physiologic sex differences are preserved. There is no indication for bone loss under these conditions.

Porcine proinsulin, related intermediates and plasma immunoreactive insulin components have been studied by radioreceptor assay. Using the purified rat liver membrane or cultured human lymphocyte radioreceptor assay, porcine proinsulin is %5, split proinsulin 6% (54-55 split in connecting peptide) desdipeptide proinsulin 20% (deletion of amino acids 62 and 63 of connecting peptide) and desnonapeptide proinsulin 27% (deletion of amino acids 55-63 of connecting peptide) as active as porcine insulin in both assay systems; these values closely parallel the in vitro bioactivity of these preparations. In the lymphocyte radioreceptor assay the human plasma immunoreactive insulin-like component has the same potency as porcine insulin per immunoreactive unit, whereas the plasma immunoreactive proinsulin-like component is only 15% as active. Since both plasma immunoreactive components are somewhat less reactive than would be expected from puriified human insulin and proinsulin, the data suggest that both plasma components contain immunoreactive molecules that do not react in the radioreceptor assay.

Little is known about hormonal regulation of substrate transport and metabolism in the mucosal lining of the small intestine. Because insulin regulates these functions in other tissues by binding to its receptor, we have investigated the presence of insulin receptors in canine small intestinal mucosa with basolateral membranes (BLM) and brush border membranes (BBM) prepared by sorbitol density centrifugation. A14-[125l]iodoinsulin was used to study binding and structural characteristics of specific insulin receptors in BLM. Analysis of receptors in BLM identified binding sites with high affinity (Kd 88 pM) and low capacity (0.4 pmol/mg protein) as well as with low affinity (Kd 36 nM) and high capacity (4.7 pmol/mg protein). Binding was time, temperature, and pH dependent, and 125l-labeled insulin dissociation was enhanced in the presence of unlabeled insulin. Cross-reactivity of these receptors to proinsulin, IGF-II, and IGF-I was 4,1.8, and

Cytoplasmic free calcium concentration [Ca2+]i was quantified in cultured bone cells with osteoblastic characteristics. The cells were obtained from femurs of obese (fa/fa) Wistar-Kyoto rats, from nonobese, noninsulin-dependent diabetic (NIDD) Sprague Dawley rats, and from their appropriate controls. [Ca2+]i was also determined in bone cells obtained fromin vivo insulin-treated NIDD rats. Obese (Wistar Kyoto) rats had increased body weight (313±13 vs. 249±4 g;P

125I-insulin binds to circulating human lymphocytes and is displaced by unlabeled insulin. We have compared the binding and displacement curves of 125I-insulin from the circulating lymphocytes of normal subjects with those of insulin resistant obese and acromegalic patients and insulin sensitive hypopituitary subjects. The initial 125I-insulin binding (maximal percent 125I-insulin bound) for normal subjects had a mean value of 2.9 ng/ml (range 1.9–3.4) per 70 × 106 cells which is not statistically different from the other patient groups. For the normals, the [Insulin]-50% inhibition 125I-insulin bound (that concentration of insulin necessary to inhibit 50% of the maximal binding) had a mean value of 8.4 ng/ml (range 6.0–12.0 ng/ml). This value is significantly different from the obese patients but not from the acromegalic or the hypopituitary subjects. If the circulating lymphocyte mirrors the changes seen in the major metabolic sites of insulin action, these data suggest that an alteration in the insulin...

To assess the affect of mild diabetes on calcium metabolism in an animal model, we evaluated calcium homeostasis before pregnancy and during gestation and lactation in non-insulindependent (NIDD) diabetic rat mothers and their neonates (NeoDM). Plasma glucose, calcium (Ca), magnesium (Mg), phosphate (Pi), and immunoreactive parathyroid hormone (iPTH) were measured in the NIDD rats and controls before pregnancy, during the first, second, and third gestational week, and during lactation 12, 24, 48 and 72 h postpartum. The same measurements were performed on NeoDM and controls 12, 24, 48, and 72 h after birth. In the mothers, plasma calcitonin was assayed before pregnancy and at 72 h postpartum. Higher plasma glucose values before pregnancy (216 +/- 9 mg/dl vs 126 +/- 4) and during the second (105 +/- 5 vs 73 +/- 6) and third (114 +/- 8 vs 91 +/- 3) gestational week were observed in diabetic mothers when compared to controls. Glucose values decreased during the second and third gestational week in both groups compared to pregestational values. Plasma Ca, Mg, and Pi were similar in both groups during gestation and lactation except for the third gestational week when plasma Mg was lower in the diabetic mothers (P less than 0.05). Plasma iPTH rose to similar values in both groups during pregnancy. During lactation, plasma iPTH levels were higher and plasma calcitonin levels were lower compared to controls (P less than .05, P less than 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

The direct effect of insulin on the high-affinity Ca2+-Mg2+-ATPase was studied in kidney proximal tubular basolateral membranes (BLM) obtained from control and streptozocin-induced non-insulin-dependent diabetes mellitus (NIDDM) rats. Plasma glucose of the diabetic animals was only mildly elevated (217 ± 9 vs. 138 ± 3 mg/dl). Both high- and low-affinity calcium-dependent Ca2+-Mg2+-ATPase activities were identified in the BLM. Enzyme activity in BLM from diabetic rats was higher at all Ca2+ concentrations tested due to a higher maximum velocity of the enzyme from NIDDM rats. The high-affinity Ca2+-Mg2+-ATPase activity was inhibited by trifluoroperzine (TFP) in both membranes. No difference in calmodulin content was found in the membranes from the diabetic and control rats. Insulin (16–200 μU/ml) significantly increased the high-affinity Ca2+-Mg2+-ATPase activity (17–40%) in membranes from control animals but had no effect on the enzyme activity in the membranes from the NIDDM rats. The basal activity of the enzyme at 0.1 μM free Ca2+ was higher in the BLM from the NIDDM animals compared to controls (17.8 ± 0.5 vs. 14.7 ± 0.8 nM Pi mg1 · min−1; P < .02). There was no effect of insulin on the Ca2+-independent ATPase activity of BLM preparations. These findings demonstrate a defect in the ability of insulin to regulate the high-affinity Ca2+-Mg2+-ATPase activity in BLM from diabetic rats. Such a defect in enzyme activity may play a role in the mechanism of impaired insulin action observed in these NIDDM rats.

Radioreceptor assays for human GH (hGH) have been developed using the IM-9 cultured human lymphoid cell receptor. Varying degrees of nonspecific interference with [125I] hGH binding to these cells occurs in the presence of serum. We have modified the traditional IM-9 competitive binding assay for hGH and abolished the nonspecific serum effects. The modified competitive assay is sensitive to as little as 2 ng/ml hGH, and it has been validated by the quantitative recovery of purified pituitary hGH in hypopituitary serum. Sera from stimulated normals, acromegalics, and patients with severe growth retardation were assayed. The RIA to radioreceptor assay ratios for these groups were 0.98 +/- 0.10, 0.97 +/- 0.18, and 2.43 +/- 0.54, respectively. The assay has potential usefulness in screening and predicting growth-retarded patients most likely to respond to exogenous hGH therapy. In addition, a sensitivity receptor modulation assay, which uses the ability of hGH to regulate its homologous IM-9 receptors, is described. This is 8- to 10-fold more sensitive than the nonregulatory assays and has been applied to the measurement of hGH in sera from unstimulated normals and acromegalics. The ratios of RIA to receptor modulation assay for the two groups were 1.17 +/-0.68 ad 1.07 +/- 0.26, respectively. These sensitive receptor assays offer a powerful technique for the measurement of biologically active and inactive GH peptide in serum, and may be particularly useful in the evaluation of statural growth disorders.

Duplicate or triplicate measurements of fasting plasma glucose, calcium (Ca), phosphate (Pi), and glycosylated hemoglobins were performed on a group of non-insulin dependent diabetic patients and controls at 3-6 month intervals. In the diabetic group (48 males and 44 females), 18 were on diet only, 21 on diet and oral hypoglycemic treatment, and 51 on diet and insulin. These were a total of 217 measurements for each parameter. Results were compared to 416 measurements obtained from sex and age-matched controls. Plasma Ca levels were higher in the diabetic group (2.48 +/- 0.004 vs 2.38 +/- 0.006 mmol/liter) P less than 0.001; plasma Pi levels were similar to those of controls. The difference in plasma Ca was not influenced by age, sex, or mode of treatment. No correlation was found in the three treatment groups between plasma Ca and duration of diabetes nor with patients' weights. The results are consistent with the view that an alteration in calcium homeostasis accompanies the diabetic state.

Studies were performed to test the hypothesis that impaired insulin action occurs as an acquired phenomenon in the streptozocin (STZ)-treated, non-insulin-dependent (NIDDM) diabetic rat model. A number of methods were used to evaluate impaired carbohydrate tolerance in these animals. Plasma glucose and insulin levels were measured at 6 and 14 wk of age, and insulin glucose tolerance tests were performed at 4 and 5 wk of age (before overt hyperglycemia ensues), and at 8 and 14 wk of age (after the animals manifest overt diabetes). The STZ-treated rats had higher plasma glucose levels than those of control animals (P < 0.001) at 6 and 14 wk of age, while their plasma insulin values were decreased to levels 73% of the controls (1.7 ng/ ml versus 2.3 ng/ml, P < 0.04). Glucose disappearance rates after high (0.35 U/kg) and low (0.175 U/kg) insulin challenge were reduced in the experimental diabetic animals at all ages with both insulin doses. The data suggest that these animals have an early and progressive acquired impairment in insulin action, most compatible with a defect in cellular biologic response to insulin. The possibility that this abnormality is secondary to insulin deficiency is raised.

Effects of rapid normalization of plasma glucose levels (by insulin infused via Alzet pumps implanted intraperitoneally) on plasma insulin-like growth factor I (IGF-I) levels, granulation tissue polyol levels, and vascular permeation by 125I-labeled albumin were examined in male Sprague-Dawley rats with streptozocin-induced (60–65 mg/kg) diabetes. Two days after implantation of pumps, plasma insulin levels were twice normal levels and remained elevated (1.4–2.5 times normal) throughout the remainder of the study. Plasma glucose levels and granulation tissue polyol levels were normalized within 2 days after initiation of insulin treatment. Plasma IGF-I levels were significantly increased (2 times) by 2 days, but were not normalized until 7 days. In contrast, 125I-albumin permeation normalized at a much slower relatively linear rate and was still not completely normal after 14 days of insulin treatment. In view of 1) previous studies demonstrating that diabetes-induced increases in 125I-albumin permeation in this tissue are linked to increased metabolism of glucose to sorbitol and 2) the rapid normalization of tissue polyol levels in this study, the relatively linear rate of normalization of vascular permeability over 14 days in these studies suggests that impaired vascular barrier functional integrity in this model is mediated by structural and/or functional vascular alterations associated with sustained increased polyol metabolism rather than by increased polyol levels per se and/or by readily reversible functional and metabolic alterations associated with acute increases in polyol metabolism. The relatively long lag time after normalization of plasma glucose and tissue polyol levels before near normalization of vascular permeability in this model isconsistent with corresponding observations on the relationship between improved glycemic control and normalization of microangiopathy and neuropathy in diabetic humans and animals. The slow relatively linear rate of normalization of vascular permeability after normalization of plasma insulin and glucose levels and tissue polyol levels suggests that normalization of impaired vascular barrier function in this model is accomplished by a repair process (probably involving turnover of altered vascular constituents), the precise nature of which remains to be elucidated.