An update on clinical presentation and responses to therapy of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH).

Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics and Genomics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH.

Triglyceride Clearance in Hypertriglyceridemic Pancreatitis: Time Course and Its Implications for Management.

OBJECTIVE: To characterize the time course of triglyceride (Tg) lowering in hypertriglyceridemic (HTg) pancreatitis according to the initial Tg values, causes, and interventions. METHODS: Patients hospitalized from October 2013 through December of 2018 with a diagnosis of pancreatitis associated with HTg (Tg level, ≥500 mg/dL), in the absence of other causes, were identified by medical record review. Tg lowering was retrospectively assessed for differences in relation to the initial Tg values, use of intravenous insulin, ethanol-associated versus nonethanol-associated causes, and time to Tg values of <500 versus <1000 mg/dL. RESULTS: Sixty-six cases were identified, and 45 had multiple measurements for time-course evaluation. Those with initial Tg values of <4000 mg/dL achieved Tg levels of <1000 mg/dL in <3 days, whereas 18.8% with higher values took 5-9 days. Insulin therapy was associated with a longer duration of HTg, whereas ethanol was associated with a shorter duration. Tg clearance in ethanol-associated HTg appeared independent of insulin treatment. Time to Tg levels of <500 mg/dL versus <1000 mg/dL was significantly longer when the initial Tg levels were >2000 mg/dL. CONCLUSION: A threshold of 4000 mg/dL for the initial Tg levels in HTg pancreatitis appears to separate patients who are likely to achieve Tg levels of <1000 mg/dL in <3 versus >3 days, independent of cause or treatment. Insulin therapy is appropriate for patients with hyperglycemia but appears unnecessary for those with isolated ethanol-associated HTg. A threshold Tg level of <1000 mg/dL appears more practical than that of <500 mg/dL for resuming nutritional intake.

Spontaneous Adrenal Hemorrhage with Mild Hypoadrenalism in a Patient Anticoagulated with Apixaban for Antiphospholipid Syndrome: A Case Report and Literature Review.

Background: Adrenal hemorrhage (AH) is a serious endocrine complication of antiphospholipid syndrome (APLS). Case Presentation. We report a 45-year-old man who presented with several deep venous thromboses and was initially treated with apixaban, who later developed bilateral AH. Laboratory findings were consistent with cortisol deficiency yet preserved aldosterone physiology. He was diagnosed with APLS and treated with warfarin. After 8 months of follow-up, he remained on cortisol replacement with no evidence of recovery. We reviewed PubMed/MEDLINE indexed articles from 1950 to 2022 for cases of AH in APLS patients on anticoagulation. Six cases of patients on direct oral anticoagulants (DOACs) were reported. Discussion. The unique vasculature of the adrenal glands creates a "functional vascular dam" in the zona reticularis, which is susceptible to thrombosis in situ and hemorrhage. DOACs may further increase the risk of AH. Conclusion: Depending on the degree of adrenal involvement in AH, patients can present with partial or complete primary adrenal insufficiency. More data are needed to characterize adrenal function after AH, and the safety of DOAC versus warfarin in patients with APLS warrants further studies.

Development and Resolution of Secondary Adrenal Insufficiency after an Intra-Articular Steroid Injection.

Corticosteroid injections are commonly indicated in inflammatory conditions involving the soft tissues, tendon sheaths, bursae, and joints. Local corticosteroids carry a lower risk of complications than systemic corticosteroid but may be systemically absorbed and subsequently suppress the hypothalamic-pituitary-adrenal (HPA) axis. This can cause secondary adrenal insufficiency (SAI) as well as iatrogenic Cushing's syndrome. We report a 78-year-old female who presented with nonspecific gastrointestinal symptoms after a recent intra-articular steroid injection in her shoulder. She had hyponatremia, low morning cortisol, and failed to respond to high-dose cosyntropin. Further workup revealed the underlying cause to be SAI. Follow-up testing revealed a recovery of HPA responsiveness within 2 weeks of her initial diagnosis. Conclusion. Our case highlights how the hypothalamic-pituitary axis (HPA) can be suppressed with intra-articular steroids. The threshold to test corticosteroid users for adrenal insufficiency should be low in clinical practice, especially for those patients with nonspecific symptoms after steroid injections. Once diagnosed, temporary treatment with steroids may be required.

Early-Onset Vascular Dementia in a 43-Year-Old Man with Accelerated Atherosclerotic Disease, Elevated Lipoprotein (a), and a Missense DNAJC5 Variant with Potential Association to Adult-Onset Ceroid Lipofuscinosis.

Early-onset dementia is defined as dementia occurring prior to the age of 65. Given its impact on physical, mental, and socioeconomic well-being, it is crucial to identify modifiable risk factors. Here, we report a 43-year-old man with early-onset dementia associated with elevated lipoprotein (a) and a missense variant in the DNAJC5 gene. He presented to the hospital with memory loss and multiple cerebrovascular infarcts. Eight months prior, an MRI revealed small acute and subacute infarcts involving the left PCA for which he was treated with antiplatelet agents and a statin. Three months later, he was readmitted for progressive memory loss. CT imaging showed evolving and new infarcts compared to prior scans. A cardiac echocardiogram excluded thrombus and PFO, and he was diagnosed with early vascular dementia. He was readmitted again 5 months later with additional evaluation revealing multifocal moderate to severe stenosis and irregularities involving the bilateral ICA and bilateral PCAs. MRI showed more pronounced infarcts compared to a previous MRI as well as new infarcts. CSF studies, VDRL, RF, ANA, ANCA, homocysteine, and MMA levels were normal. Lipoprotein (a) was found to be markedly elevated, and genetic testing revealed a missense variant of the DNAJC5 gene, the mutation of which is associated with ceroid lipofuscinosis. In conclusion, in patients with early-onset dementia and evidence of accelerated atherosclerosis, it is reasonable to measure Lp(a) and consider testing for variants in genes such as DNAJC5 and others, particularly when disease severity appears unexplained by known risk factors or circumstances.

A Novel Variant in the Calcium-Sensing Receptor Associated with Familial Hypocalciuric Hypercalcemia and Low-to-Normal PTH.

Familial hypocalciuric hypercalcemia (FHH) is considered a relatively benign condition characterized by mild elevations in serum calcium and relatively low urinary calcium excretion. It results from an elevated set point in serum calcium arising from variants in the calcium-sensing receptor (CaSR) gene but also AP2S1 and GNA11 genes, which encode for adaptor-related protein complex 2 and G11 proteins, respectively. The manifestations of FHH can vary and sometimes overlap with primary hyperparathyroidism making the diagnosis challenging. Case Presentations. We report a mother and daughter with a novel heterozygous variant in the CaSR gene resulting in a serine to leucine substitution at position 147 (S147L) of the CaSR. Both patients had mild hypercalcemia, relatively low urinary calcium excretion, elevated calcitriol, and low-to-normal intact PTH. The proband (daughter) presented with symptoms associated with hypercalcemia and was incidentally found to have a bony lesion suspicious for osteitis fibrosa cystica, and she was also diagnosed with sarcoidosis. Subtotal parathyroidectomy revealed normal-weight parathyroid glands comprised of 50-80% parathyroid epithelial cells, which has been documented as within the spectrum of normal. Her mother had no symptoms, and no intervention was pursued. Conclusion. We report a novel variant in the CaSR associated with FHH in two patients with similar biochemical features yet differing clinical manifestations. While the relationship of the bony findings and parathyroid histology with this variant remains unclear, these cases enrich our knowledge of CaSR physiology and provide further examples of how varied the manifestations of FHH can be.

Fournier's Gangrene and Diabetic Ketoacidosis Associated with Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: Life-Threatening Complications.

BACKGROUND Sodium glucose co-transporter 2 (SGLT2) inhibitors have become an appealing treatment for diabetes due to their favorable cardiac and renal outcomes. However, reports continue to emerge describing potentially life-threatening adverse events such as Fournier's gangrene and diabetic ketoacidosis associated with their use. Herein, we present a case of simultaneous Fournier's gangrene and diabetic ketoacidosis after initiation of treatment with canagliflozin. CASE REPORT A 37-year-old female with diabetes presented to the hospital with a chief complaint of left gluteal pain associated with dysuria 1 month after canagliflozin was added to her regimen. On initial evaluation, the patient was afebrile and hemodynamically stable. Physical examination revealed suprapubic tenderness and induration in the left gluteal region extending to the perineum. Laboratory testing was significant for anion gap metabolic acidosis with the presence of serum ketones. Computed tomography of abdomen and pelvis revealed features suggestive of Fournier's gangrene. The patient was treated for Fournier's gangrene and diabetic ketoacidosis. Management included empirical antibiotic treatment, multiple surgical explorations with debridement as well as insulin infusion with aggressive fluid resuscitation. The patient was discharged with a urinary catheter, vacuum dressing, and colostomy with instructions to start a basal bolus insulin regimen and discontinue canagliflozin. CONCLUSIONS This is the first case describing a simultaneous occurrence of Fournier's gangrene and diabetic ketoacidosis with SGLT2 inhibitor therapy. Considering the growing popularity of these drugs, it is important to be aware of their more serious and potentially fatal complications. It is also important to promptly terminate SGLT2 inhibitors when harmful adverse effects are suspected.

Correction: Multidisciplinary strategies to treat severe hypoglycemia in hospitalized patients with diabetes mellitus reduce inpatient mortality rate: Experience from an academic community hospital.

[This corrects the article DOI: 10.1371/journal.pone.0220956.].

Multidisciplinary strategies to treat severe hypoglycemia in hospitalized patients with diabetes mellitus reduce inpatient mortality rate: Experience from an academic community hospital.

OBJECTIVE: Severe hypoglycemia (blood glucose < 50 mg/dl) in hospitalized patients with diabetes mellitus is associated with poor outcomes such as increased mortality and readmission rates. We study the effects of system based interventions in managing severe hypoglycemia and its impact on outcomes. RESEARCH DESIGN AND METHODS: We performed retrospective review of pre- and post- intervention study to quantify severe hypoglycemia in patients admitted in the general internal medicine wards with primary or secondary diagnosis of diabetes mellitus based on ICD-9 and ICD-10 codes. We implemented multidisciplinary interventions including standardization of treatment, education of in-patient medical teams and physician notification and feedback immediately after severe hypoglycemia. The endpoints were the comparative analysis of incidence of severe hypoglycemia, in-patient mortality rate, 30-day mortality rate, 30-day readmission rate, recovery time from hypoglycemia, time to next glucose measurements, use of standardized treatment and physician notification rate pre-and post-intervention. RESULTS: The incidence of severe hypoglycemia per patient with diabetes was reduced from 9.6% (233/2416) to 5.6% (202/3607) (p<0.001) post-intervention. The in-patient mortality rate in patients with severe hypoglycemia reduced from 4.1% to 0% (p = 0.019), 30-day mortality rate reduced from 9.8% to 3.8% (p = 0.058) post-intervention. 30-day readmission rate was comparable between pre-intervention (31.7%) and post-intervention (29%) (p = 0.60). In comparison, the mortality and readmission rates of all diabetic patients did not reduce during the same observation periods. Recovery time reduced from 116 (83-161) to 75 (57-102) min (p<0.01), time to next glucose measurement reduced from 39.5 (34-48) to 32 (28-35) min (p<0.01), use of standardized treatment improved from 22.7% (53/233) to 72.2% (146/202) (p<0.001) and physician notification rate increased from 29.2 (68/233) to 84.7% (171/202) post-intervention. CONCLUSIONS: Our study shows that multidisciplinary strategies improves the process of early detection and management of severe hypoglycemia and reduce incidence and in-patient mortality rate.

A NOVEL MUTATION IN CALCIUM-SENSING RECEPTOR PRESENTING AS FAMILIAL HYPOCALCIURIC HYPERCALCEMIA IN A YOUNG MAN.

OBJECTIVE: Familial hypocalciuric hypercalcemia (FHH) is considered a relatively benign condition characterized by elevated serum calcium with relatively low urinary calcium excretion. It typically results from an altered set point in calcium homeostasis originating from mutations in the calcium-sensing receptor (CASR), AP2S1, or GNA11 genes, which encode for the calcium-sensing receptor (CaSR), adaptor-related protein complex 2, and G-protein alpha-11 subunit, respectively. Despite numerous reports of novel variants in these genes associated with FHH, new variants continue to be discovered. METHODS: We describe a 20-year-old man with a family history of hypercalcemia who had clinical findings compatible with FHH and no evidence of multiple endocrine neoplasia who underwent CASR gene sequencing for evaluation of hypercalcemia. Parathyroid gland single-photon emission computerized tomography scan was normal. RESULTS: CASR gene sequencing revealed a previously unreported heterozygous intronic variant at position 1608+3A>G (chromosome 3: 121994892) resulting in a 77-residue deletion. His mother has a history of bipolar disorder and hyperparathyroidism with an adenoma found on imaging, yet our patient had no evidence of adenoma and therefore no surgical intervention was recommended. Given that CaSR plays a role in parathyroid growth, some variants in CASR may ultimately lead to parathyroid hypertrophy and be mistaken for primary hyperparathyroidism. CONCLUSION: Long-term clinical follow up will be helpful in understanding the ultimate effects of specific CASR mutations on parathyroid growth or progression to significant hypercalcemia.

Proinsulin Expressing Neuroendocrine Tumors of the Pancreas: An Underrecognized Entity.

OBJECTIVES: Rare cases of pancreatic neuroendocrine tumors (PNETs) that produce only proinsulin (PI) and manifest with hypoglycemia have been reported. Proinsulin expression in PNET has not been systematically studied, and the clinicopathologic features of such tumors remain unknown. METHODS: We studied expression of PI by immunohistochemistry (IHC) in 136 PNETs from 2 high-volume surgical oncology centers and assessed all available clinicopathologic data. RESULTS: Thirty-six (26%) of PNETs were positive for PI by IHC, most (89%) of which coexpressed insulin IHC. Nine PI-positive tumors represented functional insulinomas. Patients with PI IHC-positive tumors demonstrated significantly lower mean preoperative serum glucose compared with PI-negative PNET patients, even when insulinomas were excluded. No differences in survival between PI IHC-positive and PI IHC-negative tumors were observed. We identified 2 PI-positive PNETs from hypoglycemic patients, which were not insulinomas or other functional variants and in which serum PI was never tested. These may have been undetected proinsulinomas. CONCLUSIONS: Proinsulin-expressing PNETs (functional or non) are not uncommon. Patients who present with hypoglycemia and normal insulin levels should be screened for proinsulinoma. Proinsulin IHC could also be used to screen for proinsulinoma. To further elucidate the clinical significance of PI expressing PNETs, prospective studies are required.

Reducing severe hypoglycaemia in hospitalised patients with diabetes: Early outcomes of standardised reporting and management.

BACKGROUND: Severe hypoglycaemic events (HGEs) in hospitalised patients are associated with poor outcomes and prolonged hospitalization. Systematic, coordinated care is required for acute management and prevention of HGEs; however, studies evaluating quality control efforts are scarce. OBJECTIVE: To investigate the effectiveness of system-based interventions to improve management response to HGEs. METHODS: System-based interventions were designed and implemented following a root cause analysis of HGE in adult patients with diabetes from two general medical wards with the highest incidence of HGE. Interventions included electronic medical record programming for a standardised order set for basal-bolus insulin regimen and hypoglycemia protocol, automated dextrose order, automated MD notification, and recommendation for endocrine consultation after two critical HGEs. The Pyxis MedStation was programmed to alert nurses to recheck blood glucose 15 min after the treatment. A card with the HGE management protocol was attached to each provider's ID badge and educational seminars were given to all providers. MAIN OUTCOMES AND MEASURES: Primary outcomes were to evaluate median time from HGE (glucose <50 mg/dL) to euglycemia (>100 mg/dL), and time from HGE to follow-up finger-stick (FS) testing preintervention and postintervention. Secondary outcomes were cumulative incidence of HGEs, recurrent hypoglycemia, rate of physician notification and use of standardised treatments among adults with diabetes on the two general medical wards. RESULTS: Among hospitalised adults with diabetes and HGE, median time from HGE to euglycemia declined from 225±46 min preintervention to 87±26 min postintervention (p=0.03). Median time from HGE to next FS testing also declined (76±14 min to 28±10 min, p<0.001). Standardised treatment administration for HGE improved significantly from 34% (12/35) to 97% (36/37); physician notification rate improved significantly from 51% (18/35) to 78% (29/37).Among hospitalised adults with diabetes, incidence of HGE decreased from 12% (35/295) over 3 months (preintervention period) to 6% (37/610) over 6 months (postintervention period) (p<0.001), while recurrent HGE did not show significant differences (37% (13/35) to 24% (9/37), p=0.09). CONCLUSIONS: System-based interventions had a clinically important impact on decreasing time from HGE to euglycemia and to next FS testing. This hypoglycemia bundle of care may be applied and tested in other community hospitals to improve patient safety.

Hyperparathyroidism-Jaw Tumor Syndrome Associated With Large-Scale 1q31 Deletion.

Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare autosomal dominant cause of familial hyperparathyroidism associated with benign, ossifying fibromas of the maxillofacial bones and increased risk of parathyroid carcinoma. The putative tumor suppressor gene CDC73 has been implicated in the syndrome, with a multitude of inactivating mutations identified; however, HPT-JT due to large-scale deletion of the chromosomal region containing the gene is exceedingly rare, and the clinical significance of this variant remains unclear. We report the case of a 32-year-old woman with a history of mandibular ossifying fibroma who presented with primary hyperparathyroidism and was found to harbor a large-scale, germline deletion on chromosome 1q31, including the CDC73 locus. HPT-JT is associated with loss of function of the putative tumor suppressor gene CDC73. Over 100 mutations and small insertions/deletions have been identified within the gene, the majority of which result in premature truncation of the parafibromin protein product. We report a case of HPT-JT associated with a large chromosomal deletion (4.1 Mb) encompassing the CDC73 gene locus. In the future, molecular testing in this autosomal dominant disorder should use techniques that allow for the detection of large-scale deletions in addition to the more commonly observed mutations and smaller-scale copy number alterations. Further investigation is needed to determine whether HPT-JT associated with a large-scale deletion carries increased risk of malignancy relative to the more common truncating mutations and what the implications are for genetic counseling.

A Systematic Review of Proinsulin-Secreting Pancreatic Neuroendocrine Tumors.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) are a heterogeneous group of islet cell-derived neoplasms with a propensity toward hormone production. Among PNETs, proinsulin-secreting tumors (proinsulinomas) are exceedingly rare. The objective of this study is to collect and summarize the existing literature to provide a comprehensive evaluation of this uncommon disease. METHODS: A systematic review was performed to characterize the clinicopathologic features of proinsulinoma. Using the electronic biomedical databases PubMed, Ovid Medline, and Embase, 316 publications were screened for relevance of which 14 were selected. We also present two patients with proinsulinoma treated at Yale New Haven Hospital. RESULTS: Of the 16 patients included in the study, the mean age was 56.8 and there was a 2:1 female predominance. The majority of patients presented with symptomatic hypoglycemia with normal or low insulin levels. Median tumor diameter was 1.2 cm and 80% were located in the body and tail of the pancreas. Following resection, most patients had normalization of hormonal levels without recurrence (75%; 12/16). CONCLUSION: Proinsulinomas are rare pancreatic neuroendocrine tumors that have the potential to cause hypoglycemia. While insulinomas and proinsulin-secreting tumors have many physiologic parallels, these cases illustrate several key distinctions in their diagnosis and management.

Current Therapies for the Medical Management of Diabetes.

Diabetes affects a large and diverse number of individuals who share in common its risks for complications but who differ greatly from one another in age, health, and a number of circumstances influential to successful treatment. Because type 2 diabetes comprises the majority of diabetes cases, a number of agents have been developed for its treatment. Their unique properties offer opportunities to overcome some of the treatment limitations of older medicines and enable a more individualized and flexible approach to glucose-lowering. At the same time, new medications are accompanied by greater costs and uncertainties about their long-term benefits or safety, and thus the present state of care for type 2 diabetes places focus on a process of shared decision-making between the clinician and patient as to which treatments can optimize health while minimizing harms. We review the major classes of diabetes agents and provide some guidance for how one might approach decision-making in choosing among them.

Second-generation antisense oligonucleotides against ß-catenin protect mice against diet-induced hepatic steatosis and hepatic and peripheral insulin resistance.

Although mutations in the Wnt/ß-catenin signaling pathway are linked with the metabolic syndrome and type 2 diabetes in humans, the mechanism is unclear. High-fat-fed male C57BL/6 mice were treated for 4 wk with a 2'-O-methoxyethyl chimeric antisense oligonucleotide (ASO) to decrease hepatic and adipose expression of ß-catenin. ß-Catenin mRNA decreased by ≈80% in the liver and by 70% in white adipose tissue relative to control ASO-treated mice. ß-Catenin ASO improved hepatic insulin sensitivity and increased insulin-stimulated whole body glucose metabolism, as assessed during hyperinsulinemic-euglycemic clamp in awake mice. ß-Catenin ASO altered hepatic lipid composition in high-fat-fed mice. There were reductions in hepatic triglyceride (44%, P < 0.05) and diacylglycerol content (60%, P < 0.01) but a 30% increase in ceramide content (P < 0.001). The altered lipid content was attributed to decreased expression of sn-1,2 diacylglycerol acyltransferase and mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase and an increase in serine palmitoyl transferase. The decrease in cellular diacyglycerol was associated with a 33% decrease in PKCε activation (P < 0.05) and 64% increase in Akt2 phosphorylation (P < 0.05). In summary, Reducing ß-catenin expression decreases expression of enzymes involved in hepatic fatty acid esterification, ameliorates hepatic steatosis and lipid-induced insulin resistance.

Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids.

A central paradox in type 2 diabetes is the apparent selective nature of hepatic insulin resistance--wherein insulin fails to suppress hepatic glucose production yet continues to stimulate lipogenesis, resulting in hyperglycemia, hyperlipidemia, and hepatic steatosis. Although efforts to explain this have focused on finding a branch point in insulin signaling where hepatic glucose and lipid metabolism diverge, we hypothesized that hepatic triglyceride synthesis could be driven by substrate, independent of changes in hepatic insulin signaling. We tested this hypothesis in rats by infusing [U-(13)C] palmitate to measure rates of fatty acid esterification into hepatic triglyceride while varying plasma fatty acid and insulin concentrations independently. These experiments were performed in normal rats, high fat-fed insulin-resistant rats, and insulin receptor 2'-O-methoxyethyl chimeric antisense oligonucleotide-treated rats. Rates of fatty acid esterification into hepatic triglyceride were found to be dependent on plasma fatty acid infusion rates, independent of changes in plasma insulin concentrations and independent of hepatocellular insulin signaling. Taken together, these results obviate a paradox of selective insulin resistance, because the major source of hepatic lipid synthesis, esterification of preformed fatty acids, is primarily dependent on substrate delivery and largely independent of hepatic insulin action.

Glycemic targets: what is the evidence?

Hyperglycemia is the unifying metabolic abnormality for all forms of diabetes mellitus, forming the basis for its diagnosis and treatment. The strong epidemiologic associations between hyperglycemia and the complications of diabetes have given rise to the glucose hypothesis-that the complications of diabetes are caused by hyperglycemia and that they can be prevented by normalizing glucose levels. Herein the authors review the epidemiologic relationships between hyperglycemia and the complications of diabetes, the major trials of glucose lowering, and the extent to which the glucose hypothesis is supported by these studies and how this information can be translated into clinical practice.