BACKGROUND: Alzheimer\'s disease (AD) is a widespread neurological illness in the elderly, which impacted about 50 million people globally in 2020. Type 2 diabetes has been identified as a risk factor. Insulin and incretins are substances that have various impacts on neurodegenerative processes. Preclinical research has shown that GLP-1 receptor agonists decrease neuroinflammation, tau phosphorylation, amyloid deposition, synaptic function, and memory formation. Phase 2 and 3 studies are now occurring in Alzheimer\'s disease populations. In this article, we present a detailed assessment of the therapeutic potential of GLP-1 analogues and DPP4 inhibitors in Alzheimer\'s disease.
OBJECTIVE: This study aimed to gain insight into how GLP-1 analogues and associated antagonists of DPP4 safeguard against AD.
METHODS: This study uses terms from search engines, such as Scopus, PubMed, and Google Scholar, to explore the role, function, and treatment options of the GLP-1 analogue for AD.
RESULTS: The review suggested that GLP-1 analogues may be useful for treating AD because they have been linked to anti-inflammatory, neurotrophic, and neuroprotective characteristics. Throughout this review, we discuss the underlying causes of AD and how GLP signaling functions.
CONCLUSIONS: With a focus on AD, the molecular and pharmacological effects of a few GLP-1/GIP analogs, both synthetic and natural, as well as DPP4 inhibitors, have been mentioned, which are in the preclinical and clinical studies. This has been demonstrated to improve cognitive function in Alzheimer\'s patients.

BACKGROUND:  Self-management is highly recommended in managing type 2 diabetes mellitus (T2DM). Amid the coronavirus disease 2019 (COVID-19) lockdown, many restrictions were imposed, which might have affected the continuum of care and self-management. However, little is known about how people with T2DM experienced self-management during COVID-19 lockdown within the primary health care (PHC) facilities.
OBJECTIVE:  The study explored and described the self-management challenges of adults with T2DM in Ekurhuleni PHC facilities amid COVID-19 level 5 and 4 lockdowns.
METHODS:  The study was conducted in three community health centres in Ekurhuleni which are rendering PHC services.
METHODS:  A phenomenological, qualitative, exploratory, and descriptive design was utilised. Purposive sampling was used to select adult patients with T2DM. Data were collected telephonically between July 2022 and August 2022 using semi-structured interviews. Inductive content analysis was used to analyse data.
RESULTS:  Two themes emerged from the interviews, namely, uncontrolled blood glucose levels and financial challenges.
CONCLUSIONS:  The patients with T2DM experienced uncontrolled blood glucose levels and financial challenges during the COVID-19 lockdown. Guidelines to improve self-management programmes during restrictions are needed to promote good health during future pandemics to prevent complications and mortality. The telehealth model can be designed to monitor chronic patients at home during lockdown as a two-way communication.Contribution: More knowledge and insight into self-management and health promotion of patients with T2DM was provided by this study. Increased training needs arose for PHC nurses in managing and monitoring patients.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a worldwide socioeconomic burden, and is accompanied by a variety of metabolic disorders, as well as nerve dysfunction referred to as diabetic neuropathy (DN). Despite a tremendous body of research, the pathogenesis of DN remains largely elusive. Currently, two schools of thought exist regarding the pathogenesis of diabetic neuropathy: a) mitochondrial-induced toxicity, and b) microvascular damage. Both mechanisms signify DN as an intractable disease and, as a consequence, therapeutic approaches treat symptoms with limited efficacy and risk of side effects.
OBJECTIVE: Here, we propose that the human body exclusively employs mechanisms of adaptation to protect itself during an adverse event. For this purpose, two control systems are defined, namely the autonomic and the neural control systems. The autonomic control system responds via inflammatory and immune responses, while the neural control system regulates neural signaling, via plastic adaptation. Both systems are proposed to regulate a network of temporal and causative connections which unravel the complex nature of diabetic complications.
RESULTS: A significant result of this approach infers that both systems make DN reversible, thus opening the door to novel therapeutic applications.

Diabetes is a series of metabolic disorders that can be categorized into three types depending on different aspects associated with age at onset, intensity of insulin resistance, and beta- cell dysfunction: Type 1 and 2 Diabetes, and Gestational Diabetes Mellitus. Type 2 Diabetes Mellitus (T2DM) has recently been found to account for more than 85% of diabetic cases. The current review intends to raise awareness among clinicians/researchers that combining vitamin D3 with metformin may pave the way for better T2DM treatment and management. An extensive literature survey was performed to analyze vitamin D\'s role in regulating insulin secretion, their action on the target cells and thus maintaining the normal glucose level. On the other side, the anti-hyperglycemic effect of metformin as well as its detailed mechanism of action was also studied. Interestingly both compounds are known to exhibit the antioxidant effect too. Literature supporting the correlation between diabetic phenotypes and deficiency of vitamin D was also explored further. To thoroughly understand the common/overlapping pathways responsible for the antidiabetic as well as antioxidant nature of metformin and vitamin D3, we compared their antihyperglycemic and antioxidant activities. With this background, we are proposing the hypothesis that it would be of great interest if these two compounds could work in synergy to better manage the condition of T2DM and associated disorders.

Βackground: β-Amyloid precursor protein-cleaving enzyme-1 (BACE1) initiates the production of Aβ-peptides that form Aβ-plaque in Alzheimer\'s disease.
Reportedly, acute insulin treatment in normal mice, and hyperinsulinemia in high-fat-fed (HFF) obese/diabetic mice, increase BACE1 activity and levels of Aβ-peptides and phospho- -thr-231-tau in the brain; moreover, these effects are blocked by PKC-λ/ι inhibitors. However, as chemical inhibitors may affect unsuspected targets, we presently used knockout methodology to further examine PKC-λ/ι requirements. We found that total-body heterozygous PKC-λ knockout reduced acute stimulatory effects of insulin and chronic effects of hyperinsulinemia in HFF/obese/diabetic mice, on brain PKC-λ activity and production of Aβ1-40/42 and phospho-thr-231-tau. This protection in HFF mice may reflect that hepatic PKC-λ haploinsufficiency prevents the development of glucose intolerance and hyperinsulinemia.
On the other hand, heterozygous knockout of PKC-λ markedly reduced brain levels of BACE1 protein and mRNA, and this may reflect diminished activation of nuclear factor kappa-B (NFκB), which is activated by PKC-λ and increases BACE1 and proinflammatory cytokine transcription. Accordingly, whereas intravenous administration of aPKC inhibitor diminished aPKC activity and BACE1 levels by 50% in the brain and 90% in the liver, nasally-administered inhibitor reduced aPKC activity and BACE1 mRNA and protein levels by 50-70% in the brain while sparing the liver. Additionally, 24-hour insulin treatment in cultured human-derived neurons increased NFκB activity and BACE1 levels, and these effects were blocked by various PKC-λ/ι inhibitors.
PKC-λ/ι controls NFκB activity and BACE1 expression; PKC-λ/ι inhibitors may be used nasally to target brain PKC-λ/ι or systemically to block both liver and brain PKC-λ/ι, to regulate NFκB-dependent BACE1 and proinflammatory cytokine expression.

A new polyacetylene glycoside, (5R)-6E-tetradecene-8,10,12-triyne-1-ol-5-O-β-glucoside (1), was isolated from the flower of Coreopsis lanceolata (Compositae), together with two known compounds, bidenoside C (10) and (3S,4S)-5E-trideca-1,5-dien-7,9,11-triyne-3,4-diol-4-O-β-glucopyranoside (11), which were found in Coreopsis species for the first time. The other known compounds, lanceoletin (2), 3,2\'-dihydroxy-4-3\'-dimethoxychalcone-4\'-glucoside (3), 4-methoxylanceoletin (4), lanceolin (5), leptosidin (6), (2R)-8-methoxybutin (7), luteolin (8) and quercetin (9), were isolated in this study and reported previously from this plant. The structure of 1 was elucidated by analyzing one-dimensional and two-dimensional nuclear magnetic resonance and high resolution-electrospray ionization-mass spectrometry data. All compounds were tested for their dipeptidyl peptidase IV (DPP-IV) inhibitory activity and compounds 2-4, 6 and 7 inhibited DPP-IV activity in a concentration-dependent manner, with IC50 values from 9.6 to 64.9 μM. These results suggest that C. lanceolata flower and its active constituents show potential as therapeutic agents for diseases associated with type 2 diabetes mellitus.

Glucokinase (GK), a cytoplasmic enzyme catalyzes the metabolism of glucose to glucose- 6-phosphate with the help of ATP and aids in the controlling of blood glucose levels within the normal range in humans. In pancreatic β-cells, it plays a chief role by controlling the glucose-stimulated secretion of insulin and in liver hepatocyte cells, it controls the metabolism of carbohydrates. GK acts as a promising drug target for the pharmacological treatment of patients with type 2 diabetes mellitus (T2DM) as it plays an important role in the control of carbohydrate metabolism.
Data used for this review was based on the search from several science databases as well as various patent databases. The main data search terms used were allosteric GK activators, diabetes mellitus, type 2 diabetes, glucokinase, glucokinase activators and human glucokinase.
This article discusses an overview of T2DM, the biology of GK, the role of GK in T2DM, recent updates in the development of small molecule GK activators reported in recent literature, mechanism of action of GK activators and their clinical status.
GK activators are the novel class of pharmacological agents that enhance the catalytic activity of GK enzyme and display their antihyperglycemic effects. Broad diversity of chemical entities including benzamide analogues, carboxamides, acrylamides, benzimidazoles, quinazolines, thiazoles, pyrimidines, pyridines, orotic acid amides, amino acid derivatives, amino phosphates and urea derivatives have been synthesized in past two decades as potent allosteric activators of GK. Presently, the pharmaceutical companies and researchers are focusing on the design and development of liver-selective GK activators for preventing the possible adverse effects associated with GK activators for the long-term treatment of T2DM.

OBJECTIVE: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated several extra-pancreatic benefits in addition to glycemic control. This study retrospectively evaluates the realworld clinical effectiveness of dulaglutide as add-on therapy in overweight patients with inadequately controlled type 2 diabetes mellitus (T2DM).
METHODS: This single-center study included overweight adult patients (N, 85; women, 45) with inadequately controlled T2DM (mean glycated hemoglobin [HbA1c] (standard deviation [SD]), 7.55 [0.43] %; and body mass index [BMI] [SD], 29.01 [2.30] kg/m2) treated with dulaglutide (1.5 mg) once weekly as an add-on therapy. Follow-up improvements in outcomes were analyzed using the paired t-test. Subgroup analysis was performed for selected outcomes. Safety parameters were also evaluated.
RESULTS: At the 20-week follow-up, dulaglutide based therapy demonstrated a significant reduction (P<.001) in HbA1c, body weight and BMI, with a mean reduction (MR [SD]) of 0.45 [0.38] %, 5.06 [2.33] kg, and 1.82 [0.81] kg/m2, respectively, in the overall population. Similarly, reduction in urine albumin/creatinine ratio [U-ACR] (6.04 [15.53] mg/g), cholesterol (3.24 [4.14] mg/dL), triglycerides (16.60 [12.39] mg/dL), very-low-density lipoprotein [VLDL] (3.31 [2.48] mg/dL), serum glutamicoxaloacetic transaminase (1.80 [2.92] U/L) and glutamic-pyruvic transaminase (8.00 [5.64] U/L) was also significant (P<.05). Target HbA1c of <7% was achieved in 40% of patients. Reduction in HbA1c and body weight was significant across all subgroups analyzed. Predominantly, gastrointestinal adverse events were reported.
CONCLUSIONS: Dulaglutide as an add-on therapy was well tolerated with significant improvement in HbA1c, body weight, BMI, U-ACR, lipid fractions and serum transaminases in overweight Indian patients with T2DM.

Type 2 diabetes mellitus is one of the most common forms of the disease worldwide. Hyperglycemia and insulin resistance play key roles in type 2 diabetes mellitus. Renal glucose reabsorption is an essential feature in glycaemic control. Kidneys filter 160 g of glucose daily in healthy subjects under euglycaemic conditions. The expanding epidemic of diabetes leads to a prevalence of diabetes-related cardiovascular disorders, in particular, heart failure and renal dysfunction. Cellular glucose uptake is a fundamental process for homeostasis, growth, and metabolism. In humans, three families of glucose transporters have been identified, including the glucose facilitators GLUTs, the sodium-glucose cotransporter SGLTs, and the recently identified SWEETs. Structures of the major isoforms of all three families were studied. Sodium-glucose cotransporter (SGLT2) provides most of the capacity for renal glucose reabsorption in the early proximal tubule. A number of cardiovascular outcome trials in patients with type 2 diabetes have been studied with SGLT2 inhibitors reducing cardiovascular morbidity and mortality. The current review article summarises these aspects and discusses possible mechanisms with SGLT2 inhibitors in protecting heart failure and renal dysfunction in diabetic patients. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. These pleiotropic effects of SGLT2 inhibitors are likely to have contributed to the results of the EMPA-REG OUTCOME trial in which the SGLT2 inhibitor, empagliflozin, slowed down the progression of chronic kidney disease and reduced major adverse cardiovascular events in high-risk individuals with type 2 diabetes. This review discusses the role of SGLT2 in the physiology and pathophysiology of renal glucose reabsorption and outlines the unexpected logic of inhibiting SGLT2 in the diabetic kidney.

Older age has a significant association with anaemia. However, this has not been adequately investigated in the context of specific comorbidities such as Type 2 Diabetes Mellitus (T2DM).
To investigate the role of age in Normocytic Anaemia (NCA) and the adverse outcomes of NCA in T2DM.
Patients with NCA, either unexplained or related to Chronic Kidney Disease (CKD), were recruited from a diabetic clinic over six months. Anaemia was defined as a haemoglobin(Hb) < 130g/l for men and <120g/l for women. The relevant data were obtained by interviewing patients and review of medical records. Patients were followed for 12 months for pre-defined adverse outcomes.
Of the 354 patients assessed, 203 were included (mean age 63.12 ± 13.62 years, males 49.8%). The prevalence of NCA was 24% (49). Older age had a significant univariate association with NCA (p < 0.001) and this remained significant (adjusted Odds Ratio (OR) 1.24, 95% CI 1.16- 5.29) after adjusting for estimated Glomerular Filtration Rate (eGFR) < 60ml/min/1.73m2, albuminuria and other potential confounders. Adjusting for eGFR as a continuous variable also confirmed this significant association (OR1.15, 95% CI 1.10-7.01). In the subgroup of patients aged ≥ 75 years, only older age was significantly associated with NCA. The incidence of all-cause mortality and composite cardiovascular/cerebrovascular events was similar in the anaemic and nonanaemic groups.
NCA is common in T2DM and has a significant association with older age independent of CKD. The anaemia is mild in most patients and appears to have a benign course.